Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors

ABSTRACT

This invention relates to novel compounds suitable for labeling or already labeled by  18 F, methods of preparing such a compound, compositions comprising such compounds, kits comprising such compounds or compositions and uses of such compounds, compositions or kits for diagnostic imaging by positron emission tomography (PET).

FIELD OF INVENTION

This invention relates to novel compounds suitable for labelling oralready labelled by ¹⁸F, methods of preparing such a compound,compositions comprising such compounds, kits comprising such compoundsor compositions and uses of such compounds, compositions or kits fordiagnostic imaging by positron emission tomography (PET).

BACKGROUND ART

Molecular imaging has the potential to detect disease progression ortherapeutic effectiveness earlier than most conventional methods in thefields of oncology, neurology and cardiology. Of the several promisingmolecular imaging technologies having been developed such as opticalimaging, MRI, SPECT and PET, PET is of particular interest for drugdevelopment because of its high sensitivity and ability to providequantitative and kinetic data.

For example positron emitting isotopes include carbon, iodine, nitrogen,and oxygen. These isotopes can replace their non-radioactivecounterparts in target compounds to produce tracers that functionbiologically and are chemically identical to the original molecules forPET imaging. Among these isotopes ¹⁸F is the most convenient labellingisotope due to its relatively long half life (110 min) which permits thepreparation of diagnostic tracers and subsequent study of biochemicalprocesses. In addition, its low β+ energy (634 keV) is alsoadvantageous.

The nucleophilic aromatic and aliphatic [¹⁸F]-fluoro-fluorinationreaction is of great importance for [¹⁸F]-fluoro-labelledradiopharmaceuticals which are used as in vivo imaging agents targetingand visualizing diseases, e.g. solid tumours or diseases of brain. Avery important technical goal in using [¹⁸F]-fluoro-labelledradiopharmaceuticals is the quick preparation and administration of theradioactive compound due to the fact that the ¹⁸F isotopes have a shorthalf-life of about only 110 minutes.

Monoamine Oxidases (MAO, EC, 1.4.3.4) is a distinct class of amineoxidases. MAO is present in two forms: MAO A and MAO B (Med. Res. Rev.1984, 4, 323-358). Crystal structures of MAO A and MAO B complexed byligands have been reported (J. Med. Chem. 2004, 47, 1767-1774 and Proc.Nat. Acad. Sci. USA, 2005, 102, 12684-12689).

Search of inhibitors that are selective for both isozyme have beenactively performed (e.g. J. Med. Chem. 2004, 47, 1767-1774 and Proc.Nat. Acad. Sci. USA, 2005, 102, 12684-12689). Deprenyl (1) (BiochemPharmacol. 1972, 5, 393-408) and clorgyline (2) are potent inhibitor ofmono amine oxidase inducing irreversible inhibition of the enzymes. TheL-isomer of deprenyl (3) is a more potent inhibitor than the D-isomer.

Neuroprotective and other pharmaceutical effects have also beendescribed for inhibitors (Nature Reviews Neuroscience, 2006, 295,295-309, Br. J. Pharmacol., 2006, 147, 5287-5296). MAO B inhibitors arefor example used to increase DOPA levels in CNS (Progr. Drug Res. 1992,38, 171-297) and they have been used in clinical trials for thetreatment of Alzheimer's disease based on the fact that an increasedlevel of MAO B is involved in astrocytes accociated with Alzheimerplaques (Neuroscience, 1994, 62, 15-30).

Fluorinated MAO inhibitors have been synthesized and biochemicallyevaluated (review: Kirk et al. in press). F-18 and C-11 labeled MAOinhibitors have been studied in vivo (Journal of the NeurologicalScience, (2007), 255, 17-22; review: Methods 2002, 27, 263-277). F-18labeled deprenyl and deprenyl analogues 4-5 have also been reported(int. J. Radiat. Appl. instrument. Part A, Applied Radiat isotopes,1991, 42, 121, J. Med. Chem. 1990, 33, 2015-2019 and Nucl. Med. Biol.1990, 26, 111-116, respectively).

It would be desirable to have new F-18 labeled compounds and methodsavailable to image diseases which go along with increased level of MAOreceptor, especially to have imaging agents and methods available whichare easy to realize and which are able to image certain levels ofastrocyte activation. This task is solved with the following invention:

-   -   The present invention provides novel compounds of Formulae Ia        and Ib. If these compounds of formulae Ia and Ib are not        ¹⁸F-labelled or ¹⁹F-labelled, but instead contain an appropriate        leaving group, they are starting materials for the synthesis of        ¹⁸F-labelled or ¹⁹F-labelled compounds of formulae Ia and Ib.        ¹⁹F-labelled compounds of formulae Ia and Ib are standard        reference compounds (as identification tool and for quality        check) of the synthesis towards ¹⁸F-labelled compounds of        formulae Ia and Ib. In the following compounds of formulae Ia        and Ib which contain an appropriate leaving group and do not        contain ¹⁸F or ¹⁹F, are also referred to as “precursor compounds        having formula Ia or Ib”. Moreover, those compounds of formula        Ia and Ib that contain ¹⁹F instead of an appropriate leaving        group are also referred to as “¹⁹F standard reference compounds        having formula Ia or Ib”. Moreover, those compounds of formulae        Ia and Ib which contain ¹⁸F and which do not contain an        appropriate leaving group are also referred to as “¹⁸F-labelled        compounds of formulae Ia or Ib”.    -   The invention further provides a method of imaging diseases, the        method comprising introducing into a patient a detectable        quantity of a ¹⁸F-labeled compound of Formulae Ia or Ib or a        pharmaceutically acceptable salt, ester, amide or prodrug        thereof.    -   The invention provides also ¹⁸F-labelled or ¹⁹F-labelled        compounds of Formula Ia and Ib for use as medicament.    -   The present invention also provides diagnostic compositions        comprising a radiolabeled compounds preferably ¹⁸F-labelled        compounds of formulae Ia and Ib, and a pharmaceutically        acceptable carrier or diluent.    -   Another aspect of the invention is directed to the use of        compounds of formulae Ia and Ib for the manufacture of a        medicament, in particular of ¹⁸F- or ¹⁹-F-labelled compounds of        formulae Ia or Ib.    -   The invention also provides a process to synthesize ¹⁸F-labelled        compounds of formulae Ia and Ib from precursor compounds having        formulae Ia or Ib.    -   The invention also provides a process to synthesize ¹⁹F-labelled        compounds of formulae Ia and Ib from precursor compounds having        formulae Ia or Ib.    -   The invention also provides a process to synthesize ¹⁸F-labelled        compounds of formulae Ia or Ib by reacting compounds of Formula        IV with compounds of Formula VI. Compounds of formulae IV can be        generated by ¹⁸F- or ¹⁹F-fluorinating a compound of formula V.    -   The invention also provides a kit for preparing a        radiopharmaceutical preparation, said kit comprising a sealed        vial containing a predetermined quantity of        -   a precursor compound having formula Ia or Ib, or        -   compounds of Formula V and VI.    -   The present invention also provides a kit for imaging diseases.        More specifically the compounds of this invention are useful for        the imaging of CNS diseases including but not limited to        inflammatory and autoimmune, allergic, infectious and        toxin-triggered and ischemia-triggered diseases,        pharmacologically triggered inflammation with pathophysiological        relevance, neuroinflammatory, neurodegenerative diseases. In        another embodiment the compounds of this invention are useful        for the imaging of tissue, in particular tumors. Examples of        inflammatory and autoimmune diseases are chronic inflammatory        intestinal diseases (inflammatory bowel diseases, Crohn's        disease, ulcerative colitis), arthritis, atheroma,        atherosclerosis, inflammatory cardiomyopathy, pemphigus, asthma,        multiple sclerosis, diabetes, type I insulin-dependent diabetes        mellitus, rheumatoid arthritis, lupus diseases and other        collagenoses, Graves' disease, Hashimoto's disease,        “graft-versus-host disease” and transplant rejections. Examples        of allergic, infectious and toxin-triggered and        ischemia-triggered diseases are: sarcoidosis, asthma,        hypersensitive pneumonitis, sepsis, septic shock, endotoxin        shock, toxic shock syndrome, toxic liver failure, ARDS (acute        respiratory distress syndrome), eclampsia, cachexia, acute viral        infections (e.g., mononucleosis, fulminant hepatitis), and        post-reperfusion organ damage. An example of a pharmacologically        triggered inflammation with pathophysiological relevance is the        “first dose response” after administration of anti-T-cell        antibodies such as OKT3. An example of systemic inflammation        reactions of an origin that is as yet unclear is eclampsia.        Examples of neurodegenerative and neuroinflammatory diseases        that are associated with a astrocyte activation/MAO regulation        are dementia, AIDS dementia, amyotrophic lateral sclerosis,        encephalitis, neuropathic pain, Creutzfeldt-Jakob disease,        Down's syndrome, diffuse Lewy body disease, Huntington's        disease, leukoencephalopathy, encephalopathies, septic        encephalopathy, hepatic encephalopathy, multiple sclerosis,        Parkinson's disease, Pick's disease, Alzheimer's disease,        frontotemporal dementia, hippocampal sclerosis,        neurocysticercosis, epilepsy, stroke, ischemia, brain tumors,        depression, schizophrenia, drug abuse. The invention, therefore,        also relates to the use of imaging compounds for diagnosing        these diseases as well as for stratification of therapy and        therapy monitoring.    -   In a preferred embodiment compounds of this invention are useful        for the imaging of multiple sclerosis, Alzheimer's disease,        frontotemporal dementia, dementia with Levy bodies,        leukoencephalopathy, epilepsy, neuropathic pain, amyotrophic        lateral sclerosis, Parkinson's Disease, encephalopathies, brain        tumors, depression, drug abuse, chronic inflammatory intestinal        diseases, atheroma, atherosclerosis, arthritis, rheumatoid        arthritis, pharmacologically triggered inflammation, systemic        inflammation of unclear origin.    -   In a more preferred embodiment compounds of this invention are        useful for the imaging of multiple sclerosis, Alzheimer's        disease, amyotrophic lateral sclerosis, Parkinson's Disease,        leukoencephalopathy, encephalopathies, epilepsy, brain tumors,        drug abuse, chronic inflammatory intestinal diseases, atheroma,        rheumatoid arthritis, pharmacologically triggered inflammation        and systemic inflammation of unclear origin.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect the present invention is directed to compounds offormula Ia

or formula Ib

wherein

-   -   W is selected from the group comprising    -   —C(U¹)(U²)—C≡CH and cyclopropyl, U¹ and U² being independently        selected from hydrogen and deuterium;    -   A is selected from the group comprising substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        such as furanyl, (C₁-C₁₀)alkyl, G⁴-(C₂-C₄)alkynyl,        G⁴-(C₁-C₄)alkoxy, (G⁴-(C₁-C₄)alkyl)aryl, (G⁴-(C₁-C₄)alkoxy)aryl,        (G⁴-(C₁-C₄)alkyl)aryl, and (G⁴-(C₁-C₄)alkoxy)aryl, heteroaryl is        preferably furanyl,    -   G¹, G², G³ and G⁴ in formula Ia and formula Ib are independently        and individually, at each occurrence, selected from the group        comprising hydrogen, (C₁-C₄)alkyl, preferably methyl, L, and        —(C₁-C₆)alkyl-L,    -   with the proviso that exactly one of G¹-G⁴ in formula Ia are        selected from L and —(C₁-C₆)alkyl-L, and    -   with the proviso that exactly one of G³ and G⁴ in formula Ib are        selected from L and —(C₁-C₆)alkyl-L,    -   L being a leaving group, or L being F, preferably ¹⁸F or ¹⁹F,        wherein, preferably, if L is ¹⁹F, said compound contains exactly        one ¹⁹F-atom being attached to an sp³-hybridized carbon atom,    -   in one embodiment L being ¹⁸F;    -   in another embodiment L being ¹⁹F;    -   wherein n is an integer from 0 to 6, preferably 1-3, more        preferably 1-2,    -   and wherein m is an integer from 0 to 4, preferably 0 to 2, more        preferably 0-1,    -   and wherein e and f are integer from 0 to 1, with the proviso        that at least one of e and f is 1,    -   including all isomeric forms of said compound, including but not        limited to enantiomers and diastereoisomers as well as racemic        mixtures,    -   and any pharmaceutically acceptable salt, ester, amide, complex        or prodrug thereof.

In one embodiment W is —CH₂—C≡CH.

In one embodiment A is selected from the group comprising substituted orunsubstituted phenyl, substituted or unsubstituted furanyl,(C₁-C₄)alkyl, G⁴-(C₃-C₄), alkynyl, G⁴-(C₁-C₃)alkoxy,(G⁴-(C₁-C₃)alkyl)phenyl, (G⁴-(C₁-C₃)alkoxy)phenyl, wherein, preferably,A is selected from the group comprising phenyl, furanyl,(G⁴-(C₁-C₃)alkyl)phenyl, (G⁴-(C₁-C₃)alkoxy)phenyl, preferably,substituted phenyl, hydroxy-phenyl, halo-phenyl, methoxy-phenyl,dimethoxy-phenyl, trifluormethyl-phenyl, and ((C₁-C₄)alkyl)-phenyl, andwherein, more preferably, A is selected from the group comprisingphenyl, (G⁴-(C₁-C₃)alkoxy)phenyl, hydroxyl-phenyl, fluorophenyl,methoxyphenyl, and methylphenyl. More preferably furanyl is furan-2-ylor furan-3-yl.

In one embodiment G¹, G², G³ and G⁴ in formula Ia, and G³ and G⁴ informula Ib are independently and individually, at each occurrence,selected from the group comprising hydrogen, (C₁-C₄)alkyl, preferablymethyl, L, and —(C₁-C₄)alkyl-L,

-   with the proviso that exactly one of G¹-G⁴ in formula Ia and exactly    one of G³-G⁴ in formula Ib are selected from L and —(C₁-C₄)alkyl-L,    wherein, preferably G¹, G², G³ and G⁴ in formula Ia, and G³ and G⁴    in formula Ib are independently and individually, at each    occurrence, selected from the group comprising hydrogen, methyl, L,    and —(C₁-C₂)alkyl-L,-   with the proviso that exactly one of G¹-G⁴ in formula Ia and exactly    one of G³-G⁴ in formula Ib are selected from L and —(C₁-C₂)alkyl-L    and wherein, more preferably, G¹, G², G³ and G⁴ in formula Ia, and    G³ and G⁴ in formula Ib are independently and individually, at each    occurrence, selected from the group comprising hydrogen, methyl, L,    and -methyl-L,-   with the proviso that exactly one of G¹-G⁴ in formula Ia and exactly    one of G³-G⁴ in formula Ib are selected from L and -methyl-L.

In one embodiment L is a leaving group selected from the groupcomprising halo, in particular chloro, bromo, iodo, mesyloxy, tosyloxy,trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy,(4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy,(2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy,(2,4,6-tri-isopropyl-phenyl)sulfonyloxy,(2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy,and (4-methoxy-phenyl)sulfonyloxy.

Preferably, L is selected from the group comprising chloro, bromo,mesyloxy, tosyloxy, trifluormethylsulfonyloxy,(4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy,(4-isopropyl-phenyl)sulfonyloxy, and(2,4,6-tri-isopropyl-phenyl)sulfonyloxy.

Preferred “precursor compounds having formulae Ia or Ib” are

In one embodiment of general formula Ia or Ib, L is not F, in particularnot ¹⁸F and not ¹⁹F; these are the aforementioned “precursor compounds”.

In another embodiment of general formula Ia or Ib, L is ¹⁸F, or themesyloxy-group, shown in any of the specific precursor compounds above,is replaced by ¹⁸F. These are the ¹⁸F-labelled compounds having formulaIa or Ib.

In yet another embodiment of general formula Ia or Ib, L is ¹⁹F, or themesyloxy-group, shown in any of the specific precursor compounds above,is replaced by ¹⁹F. These are the aforementioned “standard referencecompounds having formula Ia or Ib”.

-   L is a leaving group which is known or obvious to someone skilled in    the art and which is taken from but not limited to those described    or named in Synthesis (1982), p. 85-125, table 2 (p. 86; (the last    entry of this table 2 needs to be corrected: “n-C₄F₉S(O)₂—O—    nonaflat” instead of “n-C₄H₉S(O)₂—O— nonaflat”), Carey and Sundberg,    Organische Synthese, (1995), page 279-281, table 5.8; or Netscher,    Recent Res. Dev. Org. Chem., 2003, 7, 71-83, scheme 1, 2, 10 and 15.

It should be clear that wherever in this description the terms “aryl”,“heteroaryl” or any other term referring to an aromatic system is used,this also includes the possibility that such aromatic system issubstituted by one or more appropriate substituents, such as OH, halo,alkyl, NH₂, NO₂, SO₃ etc.

The term “aryl” as employed herein by itself or as part of another grouprefers to monocyclic or bicyclic aromatic groups containing from 6 to 12carbons in the ring portion, preferably 6-10 carbons in the ringportion, such as phenyl, naphthyl or tetrahydronaphthyl, whichthemselves can be substituted with one, two or three substituentsindependently and individually selected from the group comprising halo,nitro, (C₁-C₆)carbonyl, cyano, nitrile, hydroxyl, trifluormethyl,(C₁-C₆)sulfonyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy and (C₁-C₆)sulfanyl. Asoutlined above such “aryl” may additionally be substituted by one orseveral substituents.

The term “heteroaryl” as employed herein refers to groups having 5 to 14ring atoms; 6, 10 or 14 π (pi) electrons shared in a cyclic array; andcontaining carbon atoms (which can be substituted with halo, nitro,(C₁-C₆)carbonyl, cyano, nitrile, trifluormethyl, (C₁-C₆)sulfonyl,(C₁-C₆)alkyl, (C₁-C₆)alkoxy or (C₁-C₆)sulfanyl) and 1, 2, 3 or 4 oxygen,nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are:thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl,furanyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl,phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl,3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl,pteridinyl, 4aH-carbazolyl, carbazolyl, carbolinyl, phenanthridinyl,acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl,phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups).

Heteroaryl can be substituted with one, two or three substituentsindependently and individually selected from the group comprising halo,nitro, (C₁-C₆)carbonyl, cyano, nitrile, hydroxyl, trifluormethyl,(C₁-C₆)sulfonyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy and (C₁-C₆)sulfanyl. Asoutlined above such “heteroaryl” may additionally be substituted by oneor several substituents.

As used hereinafter in the description of the invention and in theclaims, the term “alkyl”, by itself or as part of another group, refersto a straight chain or branched chain alkyl group with 1 to 10 carbonatoms such as, for example methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl,decyl. Alkyl groups can also be substituted, such as by halogen atoms,hydroxyl groups, C₁-C₄ alkoxy groups or C₆-C₁₂ aryl groups (which,intern, can also be substituted, such as by 1 to 3 halogen atoms). Morepreferably alkyl is C₁-C₁₀ alkyl, C₁-C₆ alkyl or C₁-C₄ alkyl.

As used hereinafter in the description of the invention and in theclaims, the term alkynyl is similarly defined as for alkyl, but containat least one carbon-carbon double or triple bond, respectively, morepreferably C₃-C₄ alkynyl.

As used hereinafter in the description of the invention and in theclaims, the term “alkoxy (or alkyloxy)” refer to alkyl groupsrespectively linked by an oxygen atom, with the alkyl portion being asdefined above.

Whenever the term “substituted” is used, it is meant to indicate thatone or more hydrogens on the atom indicated in the expression using“substituted” is replaced with a selection from the indicated group,provided that the indicated atom's normal valency is not exceeded, andthat the substitution results in a chemically stable compound, i.e. acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into apharmaceutical composition. The substituent groups may be selected fromhalogen atoms, hydroxyl groups, nitro, (C₁-C₆)carbonyl, cyano, nitrile,trifluoromethyl, (C₁-C₆)sulfonyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy and(C₁-C₆)sulfanyl.

Preferred examples of ¹⁸F-labelled compounds of formulae Ia or Ib are:

In a second aspect of the invention the ¹⁸F-labelled compounds offormula Ia and Ib, and the ¹⁹F standard reference compounds of formulaeIa and Ib are provided as a medicament or pharmaceutical.

The invention relates also to the use of the ¹⁸F-labelled compounds offormula Ia and Ib, and of the ¹⁹F standard reference compounds offormulae Ia and Ib I for the manufacture of a medicament or apharmaceutical for treatment.

In a more preferred embodiment the use concerns the treatment of a CNSdisease. CNS diseases include but are not limited to inflammatory andautoimmune, allergic, infectious and toxin-triggered andischemia-triggered diseases, pharmacologically triggered inflammationwith pathophysiological relevance, neuroinflammatory, andneurodegenerative diseases.

More preferably, the CNS disease is selected from multiple sclerosis,Alzheimer's disease, frontotemporal dementia, dementia with Levy bodies,leukoencephalopathy, epilepsy, neuropathic pain, amyotrophic lateralsclerosis, Parkinson's Disease, encephalopathies, brain tumors,depression, drug abuse, chronic inflammatory intestinal diseases,atheroma, atherosclerosis, arthritis, rheumatoid arthritis,pharmacologically triggered inflammation, systemic inflammation ofunclear origin.

The present invention is also directed to a method of treatment of adisease of the central nervous system, as defined above, comprising thestep of introducing into a patient a suitable quantity of a compound offormulae Ia or Ib, preferably an ¹⁸F-labelled compound of formulae Ia orIb, or of a ¹⁹F standard reference compound of formulae Ia or Ib.

In a third aspect of the invention, ¹⁸F-labelled compounds of formulaeIa or Ib are provided as diagnostic imaging agent or imaging agent,preferably as imaging agent for PET applications. The invention relatesalso to the use of ¹⁸F-labelled compounds of formulae Ia or Ib for themanufacture of an imaging agent.

In a more preferred embodiment the use concerns the imaging of CNSdiseases. CNS diseases include but are not limited to inflammatory andautoimmune, allergic, infectious and toxin-triggered andischemia-triggered diseases, pharmacologically triggered inflammationwith pathophysiological relevance, neuroinflammatory, neurodegenerativediseases

More preferably, the CNS disease is selected from multiple sclerosis,Alzheimer's disease, frontotemporal dementia, dementia with Levy bodies,leukoencephalopathy, epilepsy, neuropathic pain, amyotrophic lateralsclerosis, Parkinson's Disease, encephalopathies, brain tumors,depression, drug abuse, chronic inflammatory intestinal diseases,atheroma, atherosclerosis, arthritis, rheumatoid arthritis,pharmacologically triggered inflammation, systemic inflammation ofunclear origin.

The present invention is also directed to a method of imaging comprisingthe step of introducing into a patient a detectable quantity of an¹⁸F-labelled compound of formulae Ia or Ib and imaging said patient.

In a forth aspect of the invention, pharmaceutical compositions areprovided comprising a compound according to formulae Ia or Ib,preferably ¹⁸F-labelled compounds of formulae Ia or Ib, or ¹⁹F standardreference compounds of formulae Ia or Ib or a pharmaceuticallyacceptable salt of an inorganic or organic acid thereof, a hydrate, acomplex, an ester, an amide, a solvate or a prodrug thereof. Preferablythe pharmaceutical composition comprises a physiologically acceptablecarrier, diluent, adjuvant or excipient.

In a preferred embodiment, pharmaceutical compositions according to thepresent invention comprise a compound of formula Ia or Ib that is apharmaceutical acceptable hydrate, complex, ester, amide, solvate or aprodrug thereof.

As used hereinafter in the description of the invention and in theclaims, the terms “inorganic acid” and “organic acid”, refer to mineralacids, including, but not being limited to: acids such as carbonic,nitric, phosphoric, hydrochloric, perchloric or sulphuric acid or theacidic salts thereof such as potassium hydrogen sulphate, or toappropriate organic acids which include, but are not limited to: acidssuch as aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulphonic acids, examples of which are formic, acetic,trifluoracetic, propionic, succinic, glycolic, gluconic, lactic, malic,fumaric, pyruvic, benzoic, anthranilic, mesylic, fumaric, salicylic,phenylacetic, mandelic, embonic, methansulfonic, ethanesulfonic,benzenesulfonic, phantothenic, toluenesulfonic, trifluormethansulfonicand sulfanilic acid, respectively.

In a fifth aspect of the invention, a radiopharmaceutical composition isprovided comprising an ¹⁸F-labelled compound of formulae Ia or Ib or apharmaceutically acceptable salt of an inorganic or organic acidthereof, a hydrate, a complex, an ester, an amide, a solvate or aprodrug thereof.

Preferably the pharmaceutical composition comprises a physiologicallyacceptable carrier, diluent, adjuvant or excipient.

The compounds according to the present invention, preferably theradioactively labeled compounds according to Formula Ia or Ib providedby the invention may be administered intravenously in anypharmaceutically acceptable carrier, e.g. conventional medium such as anaqueous saline medium, or in blood plasma medium, as a pharmaceuticalcomposition for intravenous injection. Such medium may also containconventional pharmaceutical materials such as, for example,pharmaceutically acceptable salts to adjust the osmotic pressure,buffers, preservatives and the like. Among the preferred media arenormal saline solution and plasma.

Suitable pharmaceutical acceptable carriers are known to someone skilledin the art. In this regard reference can be made to e.g. Remington'sPractice of Pharmacy, 13th ed. and in J. of. Pharmaceutical Science &Technology, Vol. 52, No. 5, September-October, p. 238-311, includedherein by reference.

The concentration of the compounds of formulae Ia and Ib, preferably ofthe ¹⁸F-labelled compound according to the present invention and thepharmaceutically acceptable carrier, for example, in an aqueous medium,varies with the particular field of use. A sufficient amount is presentin the pharmaceutically acceptable carrier when satisfactoryvisualization of the imaging target (e.g. a tumor) is achievable.

The compounds according to the present invention, in particular the¹⁸F-radioactively labeled compounds according to the present invention,i.e. the ¹⁸F-labelled compounds of formulae Ia or Ib, provided by theinvention may be administered intravenously in any pharmaceuticallyacceptable carrier, e.g., conventional medium such as an aqueous salinemedium, or in blood plasma medium, as a pharmaceutical composition forintravenous injection. Such medium may also contain conventionalpharmaceutical materials such as, for example, pharmaceuticallyacceptable salts to adjust the osmotic pressure, buffers, preservativesand the like. Among the preferred media are normal saline and plasma.Suitable pharmaceutical acceptable carriers are known to the personskilled in the art. In this regard reference can be made to e.g.,Remington's Practice of Pharmacy, 11th ed. and in J. of. PharmaceuticalScience & Technology, Vol. 52, No. 5, September-October, p. 238-311.x

In accordance with the invention, the radiolabeled compounds havinggeneral chemical Formula II either as a neutral composition or as a saltwith a pharmaceutically acceptable counter-ion are administered in asingle unit injectable dose. Any of the common carriers known to thosewith skill in the art, such as sterile saline solution or plasma, can beutilized after radiolabelling for preparing the injectable solution todiagnostically image various organs, tumors and the like in accordancewith the invention. Generally, the unit dose to be administered for adiagnostic agent has a radioactivity of about 0.1 mCi to about 100 mCi,preferably 1 mCi to 20 mCi. For a radiotherapeutic agent, theradioactivity of the therapeutic unit dose is about 10 mCi to 700 mCi,preferably 50 mCi to 400 mCi. The solution to be injected at unit dosageis from about 0.01 ml to about 30 ml. For diagnostic purposes afterintravenous administration, imaging of the organ or disease in vivo cantake place in a matter of a few minutes. However, imaging takes place,if desired, in hours or even longer, after injecting into patients. Inmost instances, a sufficient amount of the administered dose willaccumulate in the area to be imaged within about 0.1 of an hour topermit the taking of scintigraphic images. Any conventional method ofscintigraphic imaging for diagnostic purposes can be utilized inaccordance with this invention.

As used hereinafter in the description of the invention and in theclaims, the term “prodrug” means any covalently bonded compound, whichreleases the active parent pharmaceutical according to formulae Ia orIb, preferably the ¹⁸F labelled compound of formulae Ia or Ib. The term“prodrug” as used throughout this text means the pharmacologicallyacceptable derivatives such as esters, amides and phosphates, such thatthe resulting in vivo biotransformation product of the derivative is theactive drug as defined in the compounds of formula (I). The reference byGoodman and Gilman (The Pharmaco-logical Basis of Therapeutics, 8 ed,McGraw-HiM, Int. Ed. 1992, “Biotransformation of Drugs”, p 13-15)describing prodrugs generally is hereby incorporated. Prodrugs of acompound of the present invention are prepared by modifying functionalgroups present in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs of the compounds of the present invention includethose compounds wherein for instance a hydroxy group, such as thehydroxy group on the asymmetric carbon atom, or an amino group is bondedto any group that, when the prodrug is administered to a patient,cleaves to form a free hydroxyl or free amino, respectively.

Typical examples of prodrugs are described for instance in WO 99/33795,WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein byreference.

Prodrugs are characterized by excellent aqueous solubility, increasedbioavailability and are readily metabolized into the active inhibitorsin vivo.

In a sixth aspect the present invention is directed to compounds ofFormula Ia or Ib, wherein L is ¹⁹F, with the proviso that such compoundcontains exactly one ¹⁹F-atom which is attached to an sp³-hybridisedcarbon atom.

The term “sp³-hybridized carbon atom” refers to a carbon atom which islinked, beside the above mentioned [F-19]-fluoro atom, to three furtheratoms via a chemical single-bond, so that this carbon atom has got fourbinding partners in total.

Preferred compounds of Formulae Ia or Ib, with L being ¹⁹F are:

If a chiral center or another form of an isomeric center is present in acompound according to the present invention, all forms of such isomer,including enantiomers and diastereoisomers, are intended to be coveredherein. Compounds containing a chiral center may be used as racemicmixture or as an enantiomerically enriched mixture or the racemicmixture may be separated using well-known techniques and an individualenantiomer maybe used alone. In cases in which compounds haveunsaturated carbon-carbon bonds double bonds, both the cis-isomer andtrans-isomers are within the scope of this invention. In cases whereincompounds may exist in tautomeric forms, such as keto-enol tautomers,each tautomeric form is contemplated as being included within thisinvention whether existing in equilibrium or predominantly in one form.

Unless otherwise specified, when referring, to the compounds of formulathe present invention per se as well as to any pharmaceuticalcomposition thereof the present invention includes all of the hydrates,solvates, complexes, and prodrugs of the compounds of the invention.Prodrugs are any covalently bonded compounds, which releases the activeparent pharmaceutical according to formulae Ia or Ib.

The term “halo” refers to fluorine (F), chlorine (Cl), bromine (Br), andiodine (I).

In a seventh aspect of the invention is directed to a method forobtaining compounds of Formula Ia or Ib, wherein L is ¹⁸F or ¹⁹F.

Surprisingly two methods have been identified for obtaining suchcompounds.

In a first embodiment, a precursor compound according to formula Ia orIb, wherein L is a leaving group as defined above, is reacted with anF-fluorinating agent.

Preferably, said F-fluorinating agent is a compound comprising F-anions,preferably a compound selected from the group comprising4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, i.e.crownether salt Kryptofix KF, KF, HF, KH F₂, CsF, NaF andtetraalkylammonium salts of F, such as [¹⁸F]-tetrabutylammoniumfluoride, and wherein F=¹⁸F or ¹⁹F.

More specifically, with respect to ¹⁸F-labelled compounds of formulae Iaand Ib, the first embodiment of a radiolabeling method for obtaining an¹⁸F-labelled compound of formula Ia or Ib comprises the step of

-   -   ¹⁸F-Radiolabelling a compound of formula Ia or Ib having an        appropriate leaving group with a fluorination agent for        obtaining an ¹⁸F-labelled compound of formula Ia or Ib,

The term “radiolabelling” a molecule, as used herein, usually refers tothe introduction of an ¹⁸F-atom into the molecule.

The fluorination agent is defined as above, wherein F=¹⁸F.

In a second embodiment, a method of synthesis of compounds of Formula Iaand Ib, wherein L is ¹⁸F or ¹⁹F, comprises the steps:

-   -   F-fluorinating a compound of formula V

with an F-fluorinating agent to yield a compound of formula IV,

-   -   substituting said compound of formula IV with a compound of        formula VI

wherein F is ¹⁸F or ¹⁹F,

-   a is an integer from 0 to 4, preferably from 0 to 2, more preferably    from 0 to 1,-   B is a leaving group, preferably halo, in particular chloro, bromo,    iodo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy,    nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy,    (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy,    (4-isopropyl-phenyl)sulfonyloxy,    (2,4,6-tri-isopropyl-phenyl)sulfonyloxy,    (2,4,6-trimethyl-phenyl)sulfonyloxy,    (4-tertbutyl-phenyl)sulfonyloxy, and (4-methoxy-phenyl)sulfonyloxy,-   W² is W as defined in any of claims 1-2, and above,-   A² is selected from the group comprising R¹²—O-aryl,    R²—O-heteroaryl, aryl, heteroaryl, such as furanyl, (C₁-C₁₀)alkyl,    (C₂-C₄)alkynyl, (C₁-C₄)alkoxy, ((C₁-C₄)alkoxy)aryl,    ((C₁-C₄)alkyl)aryl,-   wherein R⁹ and R¹⁰ are independently and individually, at each    occurrence, selected from the group comprising (C₁-C₆)alkyl and    hydrogen,-   wherein R¹¹ is selected from the group comprising (C₁-C₆)alkyl and    R¹²,-   wherein R¹² is hydrogen,-   wherein d is an integer from 0 to 4, preferably from 0-2, more    preferably from 0-1, and-   wherein said F-fluorinating agent is as defined above,-   and wherein F═¹⁸F or ¹⁹F,-   with the proviso that compounds of formula VI contain exactly one    R¹².

Preferably, B is selected from the group comprising iodo, bromo, chloro,mesyloxy, tosyloxy, trifluormethylsulfonyloxy, andnona-fluorobutylsulfonyloxy.

Preferably, A² is selected from the group comprising R¹²—O-phenyl,phenyl, furanyl, (C₁-C₄)alkyl, (C₃-C₄)alkynyl, (C₁-C₃)alkoxy andsubstituted phenyl, more preferably from the group comprisingR¹²—O-phenyl, phenyl, furanyl, ((C₁-C₃)alkoxy)phenyl, hydroxyphenyl,halo-phenyl, methoxy-phenyl, dimethoxy-phenyl, trifluormethyl-phenyl and((C₁-C₄)alkyl)phenyl, even more preferably from the group comprisingR¹²—O-phenyl, phenyl, furanyl, hydroxyphenyl, fluoro-phenyl,methoxy-phenyl, and methyl-phenyl.

Preferably, R⁹ and R¹⁰ are independently and individually, at eachoccurrence, selected from the group comprising (C₁-C₄)alkyl andhydrogen, preferably from the group comprising methyl and hydrogen.

Preferably, R¹¹ is selected from the group comprising (C₁-C₄)alkyl andR¹², preferably from the group comprising methyl and R¹².

More specifically the second embodiment of a radiolabeling method forobtaining an ¹⁸F-labelled compound of formula Ia or Ib comprises thesteps of

-   -   ¹⁸F radiolabeling a compound of formula V with a fluorination        agent to yield a compound of formula IV, and    -   substituting a compound of formula IV with a compound of Formula        VI.

The ¹⁸F-labelled compound of Formula IV is

or pharmaceutically acceptable salts of an inorganic or organic acidthereof, hydrates, complexes, esters, amides, solvates or prodrugsthereof,wherein

-   -   B is a leaving group;    -   the leaving group B is known or obvious to someone skilled in        the art and which is taken from but not limited to those        described or named in Synthesis (1982), p. 85-125, table 2 (p.        86; (the last entry of this table 2 needs to be corrected:        “n-C₄F₉S(O)₂—O— nonaflat” instead of “n-C₄H₉S(O)₂—O-nonaflat”),        Carey and Sundberg, Organische Synthese, (1995), page 279-281,        table 5.8; or Netscher, Recent Res. Dev. Org. Chem., 2003, 7,        71-83, scheme 1, 2, 10 and 15;        in a more preferred embodiment B is selected from the group        comprising:    -   a) iodo,    -   b) bromo,    -   c) chloro,    -   d) mesyloxy,    -   e) tosyloxy,    -   f) trifluormethylsulfonyloxy and    -   g) nonafluorobutylsulfonyloxy;        a is an integer from 0 to 4, preferably a is an integer of from        0 to 2 and more preferably a is an integer of from 0 to 1;

The compound of Formula V is

or pharmaceutically acceptable salts of an inorganic or organic acidthereof, hydrates, complexes, esters, amides, solvates or prodrugsthereof,wherein

-   -   B is defined as above for compounds of Formula IV, and    -   a is defined as above for compounds of Formula IV,    -   The fluorination agent is defined as above.

The compound of Formula VI is

or pharmaceutically acceptable salts of an inorganic or organic acidthereof, hydrates, complexes, esters, amides, solvates or prodrugsthereof,wherein A² is selected from the group comprising

-   -   a) R¹²—O-aryl and    -   b) R¹²—O-heteroaryl;    -   c) aryl,    -   d) heteroaryl,    -   e) (C₁-C₁₀)alkyl,    -   f) (C₂-C₄)alkynyl,    -   g) (C₁-C₄)alkoxy,    -   h) (C₁-C₄)alkoxy)aryl,    -   i) ((C₁-C₄)alkyl)aryl and    -   j) ((C₁-C₄)alkoxy)aryl;        in a preferred embodiment A² is selected from the group        comprising    -   a) R¹²—O-phenyl,    -   b) phenyl,    -   c) furanyl,    -   d) (C₁-C₄)alkyl,    -   e) (C₃-C₄)alkynyl,    -   f) (C₁-C₃)alkoxy and    -   g) substituted phenyl;        in a more preferred embodiment A² is selected from the group        comprising    -   a) R¹²—O-phenyl,    -   b) phenyl,    -   c) furanyl,    -   d) ((C₁-C₃)alkoxy)phenyl,    -   e) hydroxy-phenyl    -   f) halo-phenyl,    -   g) methoxy-phenyl,    -   h) dimethoxy-phenyl,    -   i) trifluormethyl-phenyl and    -   j) ((C₁-C₄)alkyl)-phenyl;

In an even more preferred embodiment A² is selected from the groupcomprising

-   -   a) R¹²—O-phenyl,    -   b) phenyl,    -   c) furanyl,    -   d) hydroxyl-phenyl,    -   e) fluoro-phenyl,    -   f) methoxy-phenyl and    -   g) methyl-phenyl;        W² is selected from the group comprising    -   a) —C(U³)(U⁴)—C≡CH and    -   b) cyclopropyl;        in a preferred embodiment W² is —CH₂—C≡CH;        U³ and U⁴ are independently and individually selected from the        group comprising    -   a) hydrogen and    -   b) deuterium;        in a preferred embodiment U³ and U⁴ are hydrogen;        R⁹ and R¹⁰ are independently selected from the group    -   a) (C₁-C₆)alkyl and    -   b) hydrogen;        in a preferred embodiment R⁹ and R¹⁰ are independently selected        from the group    -   a) (C₁-C₄)alkyl and    -   b) hydrogen;        in a more preferred embodiment R⁹ and R¹⁰ are independently        selected from the group    -   a) methyl and    -   b) hydrogen;        R¹¹ is selected from the group comprising    -   a) (C₁-C₆)alkyl and    -   b) R¹²;        in a preferred embodiment R¹¹ is selected from the group        comprising    -   a) (C₁-C₄)alkyl and    -   b) R¹²;        in a preferred embodiment R¹¹ is selected from the group        comprising    -   a) methyl and    -   b) R¹²;        d is an integer from 0-4, in a preferred embodiment m is an        integer from 0-2, in a more preferred embodiment m is an integer        from 0-1;        R¹² is hydrogen;        with the proviso that compounds of Formula VI contain exactly        one R¹².

In a preferred embodiment, the fluorination agent is a fluorineradioactive isotope derivative. More preferably the fluorine radioactiveisotope derivative is a ¹⁸F derivative. More preferably, the ¹⁸Fderivative is4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K 8F(crownether salt Kryptofix K¹⁸F), K¹⁸F, H¹⁸F, KH¹⁸F₂, Cs ¹⁸F, Na¹⁸F ortetraalkylammonium salt of ¹⁸F (e.g. [F-18] tetrabutylammoniumfluoride). More preferably, the fluorination agent is K¹⁸F,H¹⁸F_(, or KH) ¹⁸F₂ most preferably K¹⁸F (¹⁸F fluoride anion).

The radiofluorination reaction can be carried out, for example in atypical reaction vessel (e.g. Wheaton vial) which is known to someoneskilled in the art or in a microreactor. The reaction can be heated bytypical methods, e.g. oil bath, heating block or microwave. Theradiofluorination reactions are carried out in dimethylformamide withpotassium carbonate as base and “kryptofix” as crown-ether. But alsoother solvents can be used which are well known to experts. Thesepossible conditions include, but are not limited to: dimethylsulfoxidand acetonitril as solvent and tetraalkyl ammonium and tertraalkylphosphonium carbonate as base. Water and/or alcohol can be involved insuch a reaction as co-solvent. The radiofluorination reactions areconducted for one to 60 minutes. Preferred reaction times are five to 50minutes. Further preferred reaction times are 10 to 40 min. This andother conditions for such radiofluorination are known to experts(Coenen, Fluorine-18 Labeling Methods: Features and Possibilities ofBasic Reactions, (2006), in: Schubiger P. A., Friebe M., Lehmann L.,(eds), PET-Chemistry—The Driving Force in Molecular Imaging. Springer,Berlin Heidelberg, pp. 15-50). The radiofluorination can be carried outin a “hot-cell” and/or by use of a module (eview: Krasikowa, SynthesisModules and Automation in F-18 labeling (2006), in: Schubiger P. A.,Friebe M., Lehmann L., (eds), PET-Chemistry—The Driving Force inMolecular Imaging. Springer, Berlin Heidelberg, pp. 289-316) whichallows an automated or semi-automated synthesis.

Furthermore, the invention provides for a composition comprising acompound according to the present invention and a pharmaceuticallyacceptable carrier or diluent.

In one embodiment said compound is an ¹⁸F-labelled compound.

In another embodiment said compound is a ¹⁹F-labelled compound.

In yet another embodiment said compound is a precursor compound.

The invention also provides for a compound according to the presentinvention, preferably an ¹⁸F- or ¹⁹F-labelled compound according thepresent invention, or a composition according to the present inventionfor use as a pharmaceutical or diagnostic agent or imaging agent.

The invention also provides for the use of a compound according to thepresent invention, preferably an ¹⁸F- or ¹⁹F-labelled compound accordingto the present invention, or a composition according to the presentinvention for the manufacture of a medicament for the treatment and/ordiagnosis and/or imaging of diseases of the central nervous system(CNS).

The invention also provides for an ¹⁸F-labelled compound of formulae Iaor Ib or a composition containing such compound for use as a diagnosticagent or imaging agent, in particular for diseases of the centralnervous system.

The invention also provides for a kit comprising a sealed vialcontaining a predetermined quantity of a compound

-   a) which is a precursor compound having formula I a or Ib, or-   b) a compound of formula V and a compound of formula VI, as defined    above.

The invention also provides for a method for detecting the presence ofmonoamine oxidase in a patient's body, preferably for imaging a diseaseof the central nervous system in a patient, comprising:

-   introducing into a patient's body a detectable amount of an    ¹⁸F-labelled compound according to the present invention or a    composition comprising such compound,-   and detecting said compound or said composition by positron emission    tomography (PET).

The invention also provides for a method of treatment of a disease ofthe central nervous system comprising the step of introducing into apatient a suitable quantity of a compound according to the presentinvention, preferably of an ¹⁸F- or ¹⁹F-labelled compound according tothe present invention.

Synthesis of Compounds

Depending on which carbon atom of compounds of formula Ia the fluoroatom (F-19 or F-18) or the leaving group (compare G¹ to G⁴) is attachedto different synthesis strategies are possible: (numbered in thefollowing as “1)”-“4)”.

1) A fluoro atom (F-19 or F-18) or a leaving group (compare G³) isattached via a linker to the central nitrogen atom:

A series of different suited co-substituted 1-(alkyl)alkyl amines (A1)(see scheme 1) are commercially available. They serve as startingmaterial for the alkylation with e.g. propargyl bromide. Alternatively,ω-substituted 2-bromo-alkanes (A2) can serve as electrophile in achemical reaction with propargyl amine or cyclobutyl amine.

Compound A3 can be alkylated with [F-18]-ω-fluoro-alkyl-bromide (A6),which is generated from the corresponding triflate (A7), towardscompound A4. Compound A3 can also be alkylated with a ω-functionalizedbuilding block towards A5, so that a later leaving group (V) of A5 isthen converted to the [F-18] fluoro atom of compound A4.

A concrete example of this approach in schem 1 is shown in scheme 2:ammonium salt 6 (Sigma) is liberated towards the corresponding freeamine (7) by basic aqueous extraction. The compound 7 is then alkylatedwith [F-18]-2-fluoro-ethyl-bromide (Bioorg. Med. Chem.; 13; 20; 2005;5779-5786) using base (e.g. sodium hydride) to obtain compound 8.

2) A fluoro atom (F-19 or F-18) or a leaving group (compare substituentG¹) is attached in α-position to the central nitrogen atom:

Amino alcohols (see B1, scheme 3) of which many examples are known inliterature or which are commercially available can be alkylated withe.g. propargyl bromide towards compound B2. The introduction of aleaving group (mesyloxy shown, but also other leaving groups possible)can be generated by standard methods to obtain compound B3. The leavinggroup of compound B3 is substituted by using a fluorinating agent toobtain compound B4.

A concrete example of a synthesis according to scheme 3 is shown inscheme 4

Compound 9 (compare J. Organomet. Chem.; 317; 1986; 93-104) isN-alkylated with propargyl bromide. This reaction can be carried out indimethylformamide and potassium carbonate (e.g. Org. Lett.; 8; 14; 2006;2945-2947) in dimethylformamide to obtain alcohol 10. But also otherbases, including but not limited to caesium or sodium carbonate, sodiumhydroxid, potassium hydroxid, lithium hydroxid, tetra-alkyl ammoniumhydroxid, sodium hydrid and other solvents, including but not limited toacetone, tetrahydrofuran, eventually mixed with water, are possible. Theresulting alcohol 10 is then converted to compound 11 by use of e.g.mesylchloride, triethylamin and dichloromethane. Other possible solventsand bases including but not limited to, are dichloroethane, ethers,ethyl acetate, diisopropyl ethyl amine, DABCO ect. Under certaincircumstances the mesylate 11 serves just as intermediate which forms ancorresponding “in-situ” aziridine. This derivative (not shown) is thenopened by the chloro-anion-nucleophile which is present in solutionleading to a suited chloro-precursor molecules (compare scheme 11,compound 42 and 43). Therefore other mesylation reagents might be alsoconsidered, like mesyl anhydride (compare e.g. Tetrahedron; 63; 25;2007; 5470-5476) to generate the mesylate as stable derivative.Nevertheless the chloro precursor compounds 42 and 43 are also suited togenerate F-18 labelled molecules (compare scheme 11 compound 13 and 39.The subsequent radiofluorination reaction of compound 11 towardscompound 13 is carried out in dimethylformamide with potassium carbonateas base and “kryptofix” as crown-ether. But also other solvents can beused which are well known to experts. These possible conditions include,but are not limited to: dimethylsulfoxid and acetonitril as solvent andtetraalkyl ammonium, tertraalkyl phosphonium carbonate or caesiumcarbonate as base. Water and/or alcohol can be involved in such areaction as co-solvent. The radiofluorination reaction is conducted at105° C. for ca. 10 min. The mesylate 11 can also be converted to thenon-radioactive fluoride 12. Suited reagents for this reaction arepotassium fluoride and “kryptofix” in acetonitrile. The reaction mixtureis optionally heated by microwave technique. Alternatively, compound 12can also be obtained from compound 10 by treatment with DAST indichloromethane. This procedure is known to experts in the field (e.g.J. Med. Chem.; 49; 8; 2006; 2496-2511).

3) A fluoro atom (F-19 or F-18) or a leaving group (compare substituentG²) is attached in β-position to the central nitrogen atom:

This approach is similar to the approach dicribed in 2). One can startfrom amino alcohols C1 which are known in literature or which arecommercially available. The amino and alcohol group can be evenprotected (not shown in scheme 5, but exaplified in scheme 6). C1 can bealkylated with e.g. propargyl bromide towards compound C2. Theintroduction of a leaving group (mesyloxy shown, but also other leavinggroups possible) can be generated by standard methods to obtain compoundC3. The leaving group of compound C3 is substituted by using afluorinating agent to obtain compound C4.

A concrete example of this approach (scheme 5) is shown in scheme 6.Amino alcohol 13 (Aldrich) which is protected as cyclic carbamate isalkylated with propargyl halogenide, for example progargyl bromide(Aldrich), by methods which are known to experts in the field (comp. J.Org. Chem.; 71; 13; (2006); 5023-5026.). This reaction can be carriedout for example in DMF or THF using strong bases such as sodium hydrideobtaining oxazolidinon 14. Compound 14 can be reduced with lithiumalanate towards alcohol 15 (analogues to J. Carbohydr. Chem.; 24; 2;(2005); 187-197). Alcohol 15 can be converted to the mesylate 16 bystandard methods which comprise e.g. mesylchloride in dichloromethaneand triethyl amine as base. Triflate 16 serves as precursor for theradiofluorination. Thus, the conversion towards compound 17 is carriedout using potassium fluoride and “kryptofix” in acetonitrile. Compound18 serves as standard reference compound for the describedradiofluorination reaction. The mesylate 16 can also be converted to thenon-radioactive fluoride 16. Suited reagents for this reaction arepotassium fluoride and “kryptofix” in acetonitrile. The reaction mixtureis optionally heated by microwave technique. Alternatively, compound 16can also be obtained from compound 15 by treatment with DAST indichloromethane. This procedure is known to experts in the field (e.g.J. Med. Chem.; 49; 8; 2006; 2496-2511).

4) A fluoro atom (F-19 or F-18) or a leaving group (compare substituentG⁴) is attached in ω-position to the central nitrogen atom:

Amino alcohols (see D1, scheme 7 (hydroxyl functionality can optionallybe protected; “spacer” according to substituent A in formula Ia) ofwhich many examples are known in literature or which are commerciallyavailable can be alkylated with e.g. propargyl bromide towards compoundD2. The introduction of a leaving group (mesyloxy shown, but also otherleaving groups possible) can be generated by standard methods to obtaincompound D3. The leaving group of compound D3 is substituted by using afluorinating agent to obtain compound D4.

A concrete example of this approach is shown in scheme 8: methyl ester19 (Pharmazie (1997), 52, 12, 937) is reduced to the correspondingalcohol by use of sodium boro hydride (e.g. Tetrahedron; 63; 9; 2007;2000-2008). The amino protecting group is subsequently removed bydissolving the intermediate in MeOH(aq) and alkali (sodium or potassium)carbonate (e.g J. Org. Chem., 53, (1988), 3108). The amino group ofcompound 20 is alkylated with propargyl bromide in DMF and potassiumcarbonate (e.g. Org. Lett.; 8; 14; 2006; 2945-2947) to obtain compound21. The alcohol 21 is converted in the corresponding mesylate 22 whichis fluorinated towards 23 and 24 by using fluorinating agents.

An example for the synthesis of compounds of formula Ib is shown inscheme 10:

Compound 25 (Chem. Europ. J.; 11; 19; 2005; 5777-5785) is alkylated withsodium hydride as base in DMF by use of propargyl bromide (compare e.g.J. Org. Chem.; 71; 13; (2006); 5023-5026). Boc-protected amine 26 isdeprotected with trifluoroacetic acid or other acids to obtain compound27. This secondary amine (27) is alkylated with [F-18]-fluoro ethylbromide (compare A6 scheme 1) obtaining compound (32). Compound 27 canalso be alkylated by 2-(2-tetrahydropyranyloxy)-ethyl bromide (Aldrich)and potassium carbonate in DMF. The protection group (THP) is removedusing acid (e.g. tosyl acid in dichloromethane) and then alcohol (29) isconverted to mesylate 30 using mesylchloride and triethylamine indichloromethane. Compound 30 is either converted in compound 31 orcompound 32 by F-19 and F-18 fluorinating reagents. Optionally compound29 can be converted into compound 31 by using DAST in dichloromethane.

Another example for the synthesis of compounds of Formula Ib is depictedin scheme 10: Compound 32 (J. Am. Chem. Soc.; EN; 129; 3; 2007; 562-568)is alkylated with propargyl bromide and sodium hydride in DMF (comparee.g. J. Org. Chem.; 71; 13; (2006); 5023-5026). The Tces and TBDMSgroups are removed using Zn—Cu couple (J. Am. Chem. Soc.; 129; 3; 2007;562-568) and hydrogen chloride. Secondary amine 34 is alkylated withmethyl iodide in acetonitrile and sodium carbonate to obtain compound35. The alcohol 35 is converted into the corresponding triflate 36 byuse of trifluoromethylsulfonylchloride and triethyl amine as base. Thetriflate 36 is converted into [F-18]-fluoro derivative 37 using typical[F-18] fluorinating agents. Alcohol 35 can also be converted intofluoride 38 using nonafluorobutylsulfonyl fluoride in DBU (TetrahedronLetters, Vol. 36, No. 15, pp. 2611-2614, 1995).

The aim of the present invention was to find an improved F-18 labelledcompound in comparison to the current state of the art that can be usedto detect reactive astrocytes by means of PET Imaging targetingmonoamine oxidase B. As the data of the present invention demonstratethe afore mentioned [¹⁸F]compound 13 surprisingly showed an improvedmetabolic stability when compared to [¹¹C]Deprenyl (compare compound 3)and compound 5 ([¹⁸F]FHMP; Nuclear Medicine Biology, Vol. 26, pp111-116, (1999).

Binding of the [¹⁸F]compound 13 was investigated on human brain sectionsfrom patients with Alzheimer's disease and normal controls using astandard protocol In brief, the tissue was cut at a 18 μm thickness in aCryostat (Leica, Germany), thaw mounted onto glass slides and kept at−20° C. for at least 48 hours before use. Thereafter, the slides wereremoved and brought to room temperature. The sections were washed in 25mM HEPES buffer for 5 min, incubated with 10 Bq/μl [18F]compound 13 in25 mM HEPES/0.1% BSA for 60 min at room temperature in a humidifiedchamber and washed again 5 times for 2 min each in 25 mM HEPES/0.1% BSA.The sections were dipped two times into ice cold distilled water, driedat room temperature and exposed to PhosphorImanger plates (FUJI BAS5000) over night. For detection of the specificity of the signals anexcess (10 μM) of Deprenyl, Pargylin (both for MAO B) and Clorgyline(for MAO A), respectively, was used. After exposure, the sections wereimmunohistochemically stained using a standard protocol with ananti-GFAP antibody to detect reactive astrocytes. Amyloid 13 plaqueswere detected with BAY 949172 (Rowe C C et al. Lancet Neutol 2008; 7:129-135) using the binding protocol as described above. The specificityof [¹⁸F]compound 13 for MAO B is presented in FIGS. 1 and 2. FIGS. 3 and4 demonstrate the relation of the radioactive signals to the underlyingpathology, i.e. amyloid 13 plaques (FIG. 3) and reactive astrocytes(FIG. 4), respectively.

Biodistribution of [¹⁸F]compound 13 was investigated in NMRI miceweighting 25-31.5 g at five time points. For each time point 3 mice havebeen used. The mice were injected each with 0.178 MBq[¹⁸F]compound 13.After the respective time points the mice were sacrificed, the organstaken out and measured in a gamma counter. The results were decaycorrected. The compound showed a high initial brain uptake ofradioactivity (7.5±0.04% ID/g at 2 min p.i.) and a high initialelimination of radioactivity from the brain (2.10±0.33% ID/g at 30 minp.i.) with a decrease to 1.34±0.26% ID/g after 4 hours as shown in FIG.5.

The [¹⁸F]compound 13 has been tested in a cynomolgus monkey. 155 MBq[¹¹C]Deprenyl and 178 MBq [¹⁸F]compound 13, respectively, have beeninjected into the same monkey. Time activity curves have been monitoredby calculating the standard uptake values (SUV) as [¹⁸F]compound 13compared to the [¹¹C]compound. Plasma radioactivity profiles have beenmonitored over time. As can be seen from the comparison of the curvesfor the mother compound in FIGS. 8 and 9 the plasma radioactivity for[¹⁸F]compound 13 was about double of that observed for [¹¹C]Deprenyl atthe 30 and 45 min time points. In addition, metabolites occurring inplasma over time have been monitored (FIGS. 8 and 9) for both ligands.As can be seen from the comparison of FIG. 8 with FIG. 9 the[¹⁸F]compound 13 is more stable than [¹¹C]Deprenyl. The generation ofmetabolite b levelled around 10% for [¹⁸F]compound 13 compared to about25% for [¹¹C]Deprenyl. For example, at the 30 min time point metaboliteb was only one third as that observed for [¹¹C]Deprenyl. It is obviousthat compound 13 is also more suited for in vivo imaging than compound 5which has been reported to be degraded quickly towards a polar[¹⁸F]-labelled metabolite.

The uptake and enrichment in specific regions, e.g. striatum, was about10% higher for [¹⁸F]compound 13 as compared to [¹¹C]Deprenyl (FIG. 10).

Further blocking experiments in monkeys show that staining in monkeybrain is specific.

Preferred precursor molecules having formulae Ia are

Preferred precursor molecules which are not covered by Formula Ib are

Preferred examples of ¹⁸F-labelled compounds of formulae Ia or Ib are

Compound 10 can be also converted to the mixture of fluorides 12 and 41whereas compound 41 is a rearranged reaction product (scheme 11).Fluorides 12 and 41 can be separated on a column (compare TLC FIG. 15).The conversion of alcohol 10 with mesylchloride leads under certaincircumstances to the mixture of chlorides 42 and 43 which is a suitedpair of precursor compounds being radiofluorinated towards F-18 labelledcompound 13 and 39. F-18 labelled products 13 and 39 are separable onHPLC column (compare FIG. 11 and FIG. 12) and can be investigatedseparately.

Alcohol 10 can be also converted to tosylate 44 using tosylanhydride.This derivative is also suited precursor for the radiolabeling towardscompound 13.

Derivative 15 can be converted by using DAST towards compound 18(compare scheme 12). The conversion of compound 15 towards chloride 45is realized using mesylchloride. Chloride 45 is a suited precursormolecule for the radiofluorination towards compound 46 (compare FIG.14).

The diastereoisomer of compound 18 is compound 47 which is synthesizedfrom (1R,2R)pseudoehedrine 48 in tow steps via alcohol 49 (see scheme13). The conversion of alcohol 49 which is synthesized from(1R,2R)pseudoehedrine by alkylation with propargyl bromide towardsfluoride 47 is realized by use of DAST. Compound 49 can also beconverted to precursor molecule 50 by use of mesylchloride.

Compound 8 is the product of the radiofluorination of chloride 52. Thisprecursor chloride is derived from alcohol 51 by use of mesylchloride.The cold reference compound (53) of F-18 labelled fluoride 8 is alsoshown in scheme 14 and can be synthesized from alcohol 51 using DAST.

An example for the synthesis of a [F-18] labeled compound of formula Ibis described in scheme 15:

Amino alcohol 54 (commercially available) is converted to thesulfamidate 55 by use of SO₂Cl₂ (compare Tetrahedron Assymetry (1990),1, 12, 877-880). The Mitsonobu reaction using prop-2-yn-1-ol,triphenylphosphin and, dipropan-2-yl (E)-diazene-1,2-dicarboxylate leadsto the precursor compound 56 which then can be converted by[¹⁸F]fluorination with tetrabutylammonium hydrodide and subsequentdeprotection of the sufate moiety (compare F-19 analogue 57) towardscompound 58. A similar approach is possible to obtain the correspondingF-19 derivative 59 (compare: Posakony et al. Synthesis (2002), 6,766-770).

Further, the invention relates to

-   1. A compound of formula Ia

or formula Ib

wherein

-   -   W is selected from the group comprising    -   —C(U¹)(U²)—C≡CH and cyclopropyl, U¹ and U² being independently        selected from hydrogen and deuterium;    -   A is selected from the group comprising substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        such as furanyl, (C₁-C₁₀)alkyl, G⁴-(C₂-C₄)alkynyl,        G⁴-(C₁-C₄)alkoxy, (G⁴-(C₁-C₄)alkyl)aryl, (G⁴-(C₁-C₄)alkoxy)aryl,        (G⁴-(C₁-C₄)alkyl)aryl, and (G⁴-(C₁-C₄)alkoxy)aryl, wherein        preferably said heteroaryl is furanyl,    -   G¹, G², G³ and G⁴ in formula Ia and formula Ib are independently        and individually, at each occurrence, selected from the group        comprising hydrogen, (C₁-C₄)alkyl, preferably methyl, L, and        —(C₁-C₆)alkyl-L,    -   with the proviso that exactly one of G¹-G⁴ in formula Ia are        selected from L and —(C₁-C₆)alkyl-L, and    -   with the proviso that exactly one of G³ and G⁴ in formula Ib are        selected from L and —(C₁-C₆)alkyl-L,    -   L being a leaving group, or L being F, preferably ¹⁸F or ¹⁹F,        wherein, preferably, if L is ¹⁹F, said compound contains exactly        one ¹⁹F-atom being attached to an sp³-hybridized carbon atom,    -   wherein n is an integer from 0 to 6, preferably 1-3, more        preferably 1-2,    -   and wherein m is an integer from 0 to 4, preferably 0 to 2, more        preferably 0-1,    -   and wherein e and f are integer from 0 to 1, with the proviso        that at least one of e and f is 1, including all isomeric forms        of said compound, including but not limited to enantiomers and        diastereoisomers as well as racemic mixtures,    -   and any pharmaceutically acceptable salt, ester, amide, complex        or prodrug thereof.

-   2. The compound according to count 1, wherein W is —CH₂—C≡CH.

-   3. The compound according to any of counts 1-2, wherein A is    selected from the group comprising substituted or unsubstituted    phenyl, substituted or unsubstituted furanyl, in particular    furan-2-yl, furan-3-yl, (C₁-C₄)alkyl, G⁴-(C₃-C₄), alkynyl,    G⁴-(C₁-C₃)alkoxy, (G⁴-(C₁-C₃)alkyl)phenyl, (G⁴-(C₁-C₃)alkoxy)phenyl.

-   4. The compound according to count 3, wherein A is selected from the    group comprising substituted or unsubstituted phenyl, substituted or    unsubstituted furanyl, (G⁴-(C₁-C₃)alkyl)phenyl,    (G⁴-(C₁-C₃)alkoxy)phenyl, hydroxy-phenyl, halo-phenyl,    methoxy-phenyl, dimethoxy-phenyl, trifluormethyl-phenyl, and    ((C₁-C₄)alkyl)-phenyl.

-   5. The compound according to count 4, wherein A is selected from the    group comprising substituted or unsubstituted phenyl,    (G⁴-(C₁-C₃)alkoxy)phenyl, hydroxyl-phenyl, fluorophenyl,    methoxyphenyl, and methylphenyl.

-   6. The compound according to any of the foregoing counts, wherein    G¹, G², G³ and G⁴ in formula Ia, and G³ and G⁴ in formula Ib are    independently and individually, at each occurrence, selected from    the group comprising hydrogen, (C₁-C₄)alkyl, preferably methyl, L,    and —(C₁-C₄)alkyl-L,

-   with the proviso that exactly one of G¹-G⁴ in formula Ia and exactly    one of G³-G⁴ in formula Ib are selected from L and —(C₁-C₄)alkyl-L.

-   7. The compound according to count 6, wherein G¹, G², G³ and G⁴ in    formula Ia, and G³ and G⁴ in formula Ib are independently and    individually, at each occurrence, selected from the group comprising    hydrogen, methyl, L, and —(C₁-C₂)alkyl-L,

-   with the proviso that exactly one of G¹-G⁴ in formula Ia and exactly    one of G³-G⁴ in formula Ib are selected from L and —(C₁-C₂)alkyl-L.

-   8. The compound according to count 7, wherein G¹, G², G³ and G⁴ in    formula Ia, and G³ and G⁴ in formula Ib are independently and    individually, at each occurrence, selected from the group comprising    hydrogen, methyl, L, and -methyl-L,

-   with the proviso that exactly one of G¹-G⁴ in formula Ia and exactly    one of G³-G⁴ in formula Ib are selected from L and -methyl-L.

-   9. The compound according to any of the foregoing counts, wherein L    is a leaving group selected from the group comprising halo, in    particular chloro, bromo, iodo, mesyloxy, tosyloxy,    trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy,    (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy,    (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy,    (2,4,6-tri-isopropyl-phenyl)sulfonyloxy,    (2,4,6-trimethyl-phenyl)sulfonyloxy,    (4-tertbutyl-phenyl)sulfonyloxy, and (4-methoxy-phenyl)sulfonyloxy.

-   10. The compound according to count 9, wherein L is selected from    the group comprising chloro, bromo, mesyloxy, tosyloxy,    trifluormethylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy,    (4-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, and    (2,4,6-tri-isopropyl-phenyl)sulfonyloxy.

-   11. The compound according to any of the foregoing counts which is

-   12. The compound according to any of counts 1-10 wherein L is not F,    in particular not ¹⁸F and not ¹⁹F.-   13. The compound according to any of counts 1-11, wherein L is ¹⁸F,    or wherein the mesyloxy-group, chloro-group and tosyloxy-group shown    in any of the compounds of count 11, is replaced by ¹⁸F.-   14. The compound according to any of counts 1-11, wherein L is ¹⁹F,    or wherein the mesyloxy-group, chloro-group and tosyloxy-group shown    in any of the compounds of count 11, is replaced by ¹⁹F.-   15. A method of synthesis of a compound as defined in count 13 or    count 14, in which a compound according to count 9 or 12 is reacted    with an F-fluorinating agent, wherein F=¹⁸F or ¹⁹F.-   16. The method according to count 15, wherein said F-fluorinating    agent is a compound comprising F-anions, preferably a compound    selected from the group comprising 4, 7, 13, 16, 21,    24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, i.e. crownether    salt Kryptofix KF, KF, HF, KH F₂, CsF, NaF and tetraalkylammonium    salts of F, such as [¹⁸F]tetrabutylammonium fluoride, and wherein    F=¹⁸F or ¹⁹F.-   17. A method of synthesis of a compound as defined in count 13 or    count 14, comprising the steps:    -   F-fluorinating a compound of formula V

with an F-fluorinating agent to yield a compound of formula IV,

-   -   substituting said compound of formula IV with a compound of        formula VI

wherein F is ¹⁸F or ¹⁹F,

-   a is an integer from 0 to 4, preferably from 0 to 2, more preferably    from 0 to 1,-   B is a leaving group, preferably halo, in particular chloro, bromo,    iodo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy,    nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy,    (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy,    (4-isopropyl-phenyl)sulfonyloxy,    (2,4,6-tri-isopropyl-phenyl)sulfonyloxy,    (2,4,6-trimethyl-phenyl)sulfonyloxy,    (4-tertbutyl-phenyl)sulfonyloxy, and (4-methoxy-phenyl)sulfonyloxy,-   and wherein W² is W as defined in any of counts 1-2,-   wherein A² is selected from the group comprising R¹²—O-aryl,    R¹²—O-heteroaryl, aryl, heteroaryl, such as furanyl, (C₁-C₁₀)alkyl,    (C₂-C₄)alkynyl, (C₁-C₄)alkoxy, ((C₁-C₄)alkoxy)aryl,    ((C₁-C₄)alkyl)aryl,-   wherein R⁹ and R¹⁰ are independently and individually, at each    occurrence, selected from the group comprising (C₁-C₆)alkyl and    hydrogen,-   wherein R¹¹ is selected from the group comprising (C₁-C₆)alkyl and    R¹²,-   wherein R¹² is hydrogen,-   wherein d is an integer from 0 to 4, preferably from 0-2, more    preferably from 0-1, and-   wherein said F-fluorinating agent is as defined in count 16, and    wherein F=¹⁸F or ¹⁹F,-   with the proviso that compounds of formula VI contain exactly one    R¹².-   18. The method according to count 17, wherein B is selected from the    group comprising iodo, bromo, chloro, mesyloxy, tosyloxy,    trifluormethylsulfonyloxy, and nona-fluorobutylsulfonyloxy.-   19. The method according to any of counts 17-18, wherein A² is    selected from the group comprising R¹²—O-phenyl, phenyl, furanyl,    (C₁-C₄)alkyl, (C₃-C₄)alkynyl, (C₁-C₃) alkoxy and substituted phenyl,    more preferably from the group comprising R¹²—O-phenyl, phenyl,    furanyl, ((C₁-C₃)alkoxy)phenyl, hydroxyphenyl, halo-phenyl,    methoxy-phenyl, dimethoxy-phenyl, trifluormethyl-phenyl and    ((C₁-C₄)alkyl)phenyl, even more preferably from the group comprising    R¹²—O-phenyl, phenyl, furanyl, hydroxyphenyl, fluoro-phenyl,    methoxy-phenyl, and methyl-phenyl.-   20. The method according to any of counts 17-19, wherein R⁹ and R¹⁰    are independently and individually, at each occurrence, selected    from the group comprising (C₁-C₄)alkyl and hydrogen, preferably from    the group comprising methyl and hydrogen.-   21. The method according to any of counts 17-20, wherein R¹¹ is    selected from the group comprising (C₁-C₄)alkyl and R¹², preferably    from the group comprising methyl and R¹².-   22. A composition comprising a compound according to any of counts    1-14 and a pharmaceutically acceptable carrier or diluent.-   23. The composition according to count 22, wherein said compound is    a compound according to count 13.-   24. The composition according to count 22, wherein said compound is    a compound according to count 14.-   25. The composition according to count 22, wherein said compound is    a compound according to count 12.-   26. A compound according to any of counts 1-14, preferably a    compound according to count 13 or 14, or a composition according to    any of counts 22, 23, 24 or 25 for use as a pharmaceutical or    diagnostic agent or imaging agent.-   27. Use of a compound according to any of counts 1-14, preferably a    compound according to count 13 or 14, or a composition according to    any of counts 22, 23, 24 or 25 for the manufacture of a medicament    for the treatment and/or diagnosis and/or imaging of diseases of the    central nervous system (CNS).-   28. A compound according to count 13 or a composition according to    count 23 for use as a diagnostic agent or imaging agent, in    particular for diseases of the central nervous system.-   29. A kit comprising a sealed vial containing a predetermined    quantity of a compound according to-   a) count 12 or-   b) formula V and VI, as defined in any of counts 17-21.-   30. A method for detecting the presence of monoamine oxidase in a    patient's body, preferably for imaging a disease of the central    nervous system in a patient, comprising:-   introducing into a patient's body a detectable amount of a compound    according to count 13 or a composition according to count 23,-   and detecting said compound or said composition by positron emission    tomography (PET).-   31. A method of treatment of a disease of the central nervous system    comprising the step of introducing into a patient a suitable    quantity of a compound according to any of counts 1-14, preferably    of a compound according to count 13 or 14.

DESCRIPTION OF THE FIGURES

FIG. 1: Autoradiography using [¹⁸F]compound 13 on human brain slicesfrom four brains from patients with diagnosis of Alzheimer's disease.(A) Autoradiographic signal after exposure on the PhosphorImager plate.Note the black dots in the tissue slices corresponding to areas withamyloid β plaques (see examples in FIG. 3). (B) and (C) the signalscould be blocked with deprenyl and pargylin, respectively, showing thespecificity of [¹⁸F]compound 13 for MAO B.

FIG. 2: Autoradiography using [¹⁸F]compound 13 on human brain slicesfrom four brains from patients with diagnosis of Alzheimer's disease.(A) Autoradiographic signal after exposure on the PhosphorImager plate.Note the black dots in the tissue slices corresponding to areas withamyloid β plaques (see examples in FIG. 3). (B) the signals could becompletely blocked with deprenyl but not with clorgyline (MAO Ainhibitor) as seen in (C), showing the specificity of [¹⁸F]compound 13for MAO B.

FIG. 3: Tissue samples from three brains from patients with Alzheimer'sdisease which were processed for [¹⁸F]compound 13 autoradiography andsubsequently for binding with the amyloid detecting substance BAY949172. (A) and (B) the square marked in the brain slice is shown inhigher magnification in (a) and (b) demonstrates the underlying amyloidβ pathology. (C) two squares, (a) and (b), are marked in the brain sliceand are shown in higher magnification in (a′) and (b′). (c) and (d)represent the amyloid β pathology in the regions shown in highermagnification. Note that the signal density and intensity correspondswith the amyloid β plaque load. The square (b) is devoid of specificsignals in the autoradiography did also not show BAY 949172 binding (d).

FIG. 4: The correspondence of the autoradiographic signal to reactiveastrocytes is demonstrated. (A) On a human brain slice from a patientwith AD [¹⁸F]compound 13 binding is shown. (B) The square marked in A isshown in higher magnification. In this area immunoreactivity for GFAP,showing reactive astrocytes, is demonstrated in (C).

FIG. 5: Distribution of [¹⁸F]compound 13 detected via a gamma-detectoris shown in a time frame of 4 hours for brain and blood.

FIG. 6: The time activity curve for [¹¹C]Deprenyl (C-11 labelledcompound 3) in the btrain of the cynomolgus monkey expressed in standarduptake values (SUV %) over a time of 120 min is shown.

FIG. 7: The time activity curve [¹⁸F]compound 13 in the btrain of thecynomolgus monkey expressed in standard uptake values (SUV %) over atime of 120 min is shown.

FIG. 8: Demonstration of in vivo metabolism of [¹¹C]Deprenyl (C-11labelled compound 3) in the cynomolgus monkey. The mother compound[¹¹C]Deprenyl (C-11 labelled compound 3) as well as metabolites a and bare shown.

FIG. 9: Demonstration of in vivo metabolism of [¹⁸F]compound 13 in thecynomolgus monkey. The mother compound (C-11 labelled compound 3) aswell as metabolites a and b are shown.

FIG. 10: Images of three planes (transversal, coronal and saggital) ofthe brain of the same cynomolgus monkey after the injection of (A)[¹¹C]Deprenyl (C-11 labelled compound 3) and (B) [¹⁸F]compound 13. (C)Time activity curves for (a) [¹¹C]Deprenyl (C-11 labelled compound 3)and (b) [¹⁸F]compound 13 in the striatum and cerebellum of the monkeybrain.

FIG. 11: radio-chromatogram of crude product (starting from 42 and 43towards compound 13 and 39) on ACE 5-C18-HL 250 mm×10 mm column,Advanced Chromatography Technologies; Cat. No.: ACE 321-2510; isocratic,35% acetonitrile in 0.1% trifluoroacetic acid, flow: 4 ml/min;t_(R)=17.5 min.

FIG. 12: Analytical chromatogram of compound 13 on reverse phase HPLC ona μ-Bondapak C-18 column (300×3.9 mm, 10 μm; waters instruments) andMeCN—H₃PO₄ (0.01 M) (15:85 v/v) was used as the eluting solvent at aflow rate of 2 mL/min. The eluate was monitored by a UV absorbancedetector (λ=214 nm) in series with a radioactivity detector (β-flow;Beckman, Fullerton, Calif.).

FIG. 13: Analytical chromatogram of compound 8 on reverse phase HPLC ona P-Bondapak C-18 column (300×3.9 mm, 10 μm; waters instruments) andMeCN—H₃PO₄ (0.01 M) (15:85 v/v) was used as the eluting solvent at aflow rate of 2 mL/min. The eluate was monitored by a UV absorbancedetector (λ=214 nm) in series with a radioactivity detector (β-flow;Beckman, Fullerton, Calif.).

FIG. 14: Analytical chromatogram of compound 40 on reverse phase HPLC ona μ-Bondapak C-18 column (300×3.9 mm, 10 μm; waters instruments) andMeCN—H₃PO₄ (0.01 M) (15:85 v/v) was used as the eluting solvent at aflow rate of 2 mL/min. The eluate was monitored by a UV absorbancedetector (λ=214 nm) in series with a radioactivity detector (β-flow;Beckman, Fullerton, Calif.).

FIG. 15: TLC analysis (silica gel, molybdato phosphoric acid divingbath; ethylacetate hexane: 1:2) of fluorination reaction starting fromcompound 10 towards compound 12 and 41. (a): starting material (10)(with impurity (“circled”)) of the mentioned reaction. (b): columnfraction containing mainly compound 41. (c): column fraction containingcompound 12 and 41. (d): column fraction containing mainly compound 12.(e): column fraction containing compound 12 and 41.

EXPERIMENTAL

General Procedures:

A: Fluorination with Non-radioactive [F-19] Fluoride

To a solution of 0.25 mmol starting material in 0.5 ml acetonitril 16 mg(0.27 mmol) potassium fluoride and 104 mg (1.1 eq.) kryptofix are added.The reaction mixture is heated by microwave (130° C., 15 min) and cooledto room temperature again. The reaction mixture is diluted with 10 mldiethyl ether and 10 ml water. The organic phase is separated. Theaqueous phase is extracted three times with 10 ml diethyl ether. Thecombined organic phases are washed with brine and dried with magnesiumsulfate. The solvent is evaporated and the residue is purified by columnchromatography with ethyl acetate-hexane gradient.

B: Fluorination with Radioactive [F-18] Fluoride

To a Wheaton vial (5 ml) charged with 2.5 mg Kryptofix (2.2.2Kryptand)in 0.75 ml acetonitrile and 0.5 mg potassium carbonate and the fluorinecontaining water (0.5-2.5 GBq, 200-300 μl) is added. The solvent isremoved by heating at 120° C. for 10 mins under a stream of nitrogen.Anhydrous MeCN (1 ml) is added and evaporated as before. This step isrepeated again. A solution of starting material (2 mg) in 0.70 mlanhydrous MeCN is added. After heating at 110° C. for 30 min. The crudereaction mixture is analyzed using analytical HPLC: ACE3-C18 50 mm×4.6mm; solvent gradient: start 5% acetonitril-95% acetonitril in water in 7min., flow: 2 ml/min. The desired F-18 labeled product is confirmed byco-injection with the corresponding non-radioactive F-19 fluoro-standardon the analytical HPLC. The crude product (50-400 MBq) is purified bypreparative HPLC column: The desired product is obtained (15-200 MBq) asreconfirmed by co-injection with the non-radioactive F-19 fluorostandard on the analytical HPLC.

C: Fluorination with [F-18] Fluoride

A solution of [¹⁸F]fluoride in [¹⁸O] enriched water was flashed througha Sep-Pak QMA light cartridge (preconditioned with K₂CO₃ [0.5 M, 10 mL],18 MΩ H2O, 15 mL) to isolate [¹⁸F]fluoride which was then eluted fromthe cartridge with a solution of K₂CO₃ (7 μmol), Kryptofix 2.2.2 (130μmol) in water (18 MΩ, 43 μL) and acetonitrile (2 mL). The solvent wasevaporated at 160° C. under continues nitrogen flow and a yellow residueof [¹⁸F]F⁻/K₂CO₃/K_(2.2.2) was left. The residue was then cooled to 25°C. and the precursor (˜0.01 mmol, 2 mg) in DMSO (600 μL) was added. Theclosed reaction vessel was heated at 120° C. for 20 min and cooled downto room temperature. The reaction mixture was generally diluted withwater to a total volume of 5 mL before HPLC purification.

E.g., F-18 labelled compounds 13, 39, 8 and 40 were also purified byreverse phase HPLC on a μ-Bondapak C-18 column (300×7.8 mm, 10 μm;waters instruments) and MeCN—H₃PO₄ (0.01 M) (15:85 v/v) was used as theeluting solvent at a flow rate of 4 mL/min (compare FIGS. 11, 12, 13 and14). The eluate was monitored by a UV absorbance detector (λ=214 nm) inseries with a GM tube radioactivity detector. The fraction of thedesired compounds were collected and evaporated to dryness. The residuewas dissolved in sterile disodiumphosphate phosphate buffered saline(PBS; pH=7.4; 10 mL) and filtered through a sterile filter (0.22 μm;Millipore, Bedford, Mass.), yielding a sterile and pyrogenic solution of[¹⁸F]radioligand. The radiochemical purity of each radioligand wasanalyzed by a reverse phase HPLC on a μ-Bondapak C-18 column (300×3.9mm, 10 μm; waters instruments) and MeCN—H₃PO₄ (0.01 M) (15:85 v/v) wasused as the eluting solvent at a flow rate of 2 mL/min. The eluate wasmonitored by a UV absorbance detector (λ=214 nm) in series with aradioactivity detector (β-flow; Beckman, Fullerton, Calif.). Theradiochemical purity was >99% for all three compounds. Alternatively thecollected HPLC fraction was diluted with 40 ml water and immobilized ona Sep-Pak Plus C18 cartridge (Waters), which was washed with 5 ml waterand eluted with 1 ml ethanol to deliver the product in a radiochemicalpurity>99% as well.

The stability and radiochemical yield was analyzed with HPLC and TLC onsilica gel. TLC plate was scanned with an AR-2000 Imaging Scanner andanalyzed with Winscan 2.2 software. The incorporation yield of thefluorination reaction varied from 40% to 70%. The radiochemical puritywas more than 99% for all three radioligands. Radioligands were found tobe stable in PBS buffer solution for the duration of experiments.Radiochemical purity was >99% at 3 h after formulation with PBS whichwas determined by HPLC and TLC. Alternatively, compound 13 and 39 werealso separated via an preparative HPLC column and method (comp. FIG.11): ACE 5-C18-HL 250 mm×10 mm, Advanced Chromatography Technologies;Cat. No.: ACE 321-2510; isocratic, 35% acetonitrile in 0.1%trifluoroacetic acid, flow: 4 ml/min; t_(R)=17.5 min. The collected HPLCfraction was diluted with 40 ml water and immobilized on a Sep-Pak PlusC18 cartridge (Waters), which was washed with 5 ml water and eluted with1 ml ethanol to deliver compound 13 in a radiochemical purity >99%. Thedesired product 13 was characterized by co-injection with thenon-radioactive F-19 fluoro standard 12 on the analytical HPLC.

D: Alkylation of NH-carbamate with [F-18] Labeled Prosthetic Group

To a suspension of 1 ml dry tetrahydrofuran (THF) and 7.7 mmol sodiumhydride—which has been washed with hexane—7 mmol starting material in 1ml THF is added dropwisely. The reaction mixture is stirred for 20 min.The prepared [F-18]-fluoro-alkyl bromide (100-500 GBq; known fromliterature) in tetrahydrofuran is dropped into the suspension. Thereaction is heated to 50° C. for 20 min. The vigorously reaction mixtureis cooled to room temperature. The crude reaction mixture is analyzedusing analytical HPLC. The desired F-18 labeled product is confirmed byco-injection with the non-radioactive F-19 fluoro-standard on theanalytical HPLC.

E: Fluorination with [F-18] Fluoride Using Tetrabutylammonium HydroxideAnd Subsequent Deprotection

compare also: J. Med. Chem. 2007, 50, 1028-1040.

[¹⁸F]fluoride was transferred to a Vacutainer that had previously beentreated with tetrabutylammonium hydroxide (2 micro liter). The [¹⁸O]H₂Owas removed by azeotropic distillation with acetonitrile (3_times 0.75mL), N₂, and heat (compare Nucl. Med. Biol. 2003, 30, 397-404).Precursor (3.0 micro mol) was added to the vessel and dissolved in DMSO(400 micro liter). The resulting mixture was heated by microwaveirradiation (3 times for 20 sec). The crude mixture was passed over asilica pipet column (50 mg) with CH₃CN (3 mL), and the volatile organicswere then removed using reduced pressure. The vial containing a crudemixture of [¹⁸F]product was dissolved in CH₃CN (500 micro L) and wastreated with 4N sulfuric acid (0.5 ml). The resulting mixture was heatedby microwave irradiation (3 times for 20 sec). The desired product wasseparated via an preparative HPLC column and method: ACE 5-C18-HL 250mm×10 mm, Advanced Chromatography Technologies; Cat. No.: ACE 321-2510;isocratic, 35% acetonitrile in 0.1% trifluoroacetic acid, flow: 4ml/min). The collected HPLC fraction was diluted with 40 ml water andimmobilized on a Sep-Pak Plus C18 cartridge (Waters), which was washedwith 5 ml water and eluted with 1 ml ethanol to deliver compound 13 in aradiochemical purity >99%. The desired product 13 was characterized byco-injection with the non-radioactive F-19 fluoro standard 12 on theanalytical HPLC.

F: Alkylation of NH-carbamate

To a stirred suspension of 20 ml dry DMF and 11 mmol sodiumhydride—which has been washed with hexane—10 mmol starting material in 5ml DMF is added dropwisely at 0° C. The reaction mixture is stirred for20 min. 15 mmol alkylation agent diluted in 5 ml tetrahydrofuran isadded dropwisely to the stirred suspension. The reaction mixture isstirred for 16-10 hours. The reaction mixture is poured onto avigerously stirred mixture of ice-water and diethyl ether. The organicphase is separated. The aqueous phase is extracted three times with 30ml diethyl ether. The combined organic phases are washed with brine anddried with magnesium sulfate. The solvent is evaporated and the residueis purified by column chromatography with ethyl acetate-hexane gradient.

G: Alkylation of NH-amine with [F-18] Labeled Prosthetic Group

To a solution 2 mg secondary amine (starting material) and 3 mgpotassium carbonate in 0.7 ml dimethyl formamide was added[F-18]fluoro-alkylating agent (ca. 200-1000 MBq) in dimethyl formamideprepared from literature protocol. The reaction mixture is heated to110° C. for 20 min. The reaction mixture is cooled to room temperature.The desired F-18 labeled product is confirmed by co-injection with thenon-radioactive F-19 fluoro-standard on the analytical HPLC. The crudeproduct (ca. 50-400 MBq) is purified by preparative HPLC column. Thedesired product is obtained (ca. 15-200 MBq) as reconfirmed byco-injection with the non-radioactive F-19 fluoro standard on theanalytical HPLC.

H: Alkylation of NH-amine (Secondary Amine) or Phenols

To a stirred solution of 2 mmol starting material and 0.415 g (3 mmol)potassium carbonate in 6 ml dimethyl formamide was added 2.5 mmolalkylating agent. The reaction mixture was heated by microwave to −110°C. for 15 min. The solvent of the reaction mixture is evaporated. Water(8 ml) and diethylether or dichloromethane/isopropanol mixture (1:10-8ml) are added. The organic phase is separated. The aqueous phase isextracted three times with 30 ml diethyl ether. The combined organicphases are washed with water (twice ca. 5 ml), brine and dried withmagnesium sulfate. The solvent is evaporated and the residue is purifiedby column chromatography with ethyl acetate-hexane gradient.

I: Conversion of Alcohol to Corresponding O-sulfonate (Version 1)

To a solution of 0.5 mmol starting material and 0.103 g (0.8 mmol)diisopropyl ethyl amine in 1.5 ml dichloromethane was added (0.6 mmol)mesyl chloride or mesyl anhydride in 0.1 ml dichloromethane dropwise at−10° C. The stirred reaction mixture was warmed over a period of 4.5 hto room temperature and diluted with dichloromethane. The organic phasewas washed with saturated sodium hydrogen carbonate solution, water andbrine. The organic phase was dried with magnesium sulfate. The crudeproduct was purified by silica column chromatography (ethylacetate-hexane gradient).

K: Conversion of Alcohol to Corresponding O-sulfonate (Version 2)

To a solution of 3 mmol starting material in 5 ml dichloromethane and 5ml pyridine was added (3.3 mmol) aryl sulfonyl chloride in 3 mldichloromethane dropwisely at −10° C. The stirred reaction mixture waswarmed over a period of 4.5 h to room temperature and diluted withdichloromethane. The organic phase was washed with 0.5N sulfuric acid(three times), saturated sodium hydrogen carbonate solution, water andbrine. The organic phase was dried with magnesium sulfate. The crudeproduct was purified by silica column chromatography (ethylacetate-hexane gradient).

M: Deprotection of Acid Labile Protecting Group (Version 1)

A solution of 5 mmol starting material in wet trifluoro aceticacid-dichloromethane mixture (1:1) was stirred for 4-7 hours. Thereaction mixture is evaporated. The residue is solved in dichloromethaneand the solution is evaporated again. The last step is repeated threetimes. The residue is purified by column chromatography(dichloromethane—pentane gradient, amino phase).

N: Deprotection of Acid Labile Protecting Group (Version 2)

(According to J. Am. Chem. Soc., 6644, 92, (1970))

To a stirred solution of 0.5 mmol starting material in 1 ml ethanol isadded 1 ml of 3N aqueous hydrogen chloride at 0° C. The solution isstirred for 16 h at room temperature. The reaction is treated with NaOHaq. (4N) until pH=9.5. Ethanol is evaporated. Water (10 ml) anddichloromethan-isopropanol (10 ml; 10:1) are added. The organic phase isseparated. The aqueous phase is extracted three times with 10 mldichloromethan-isopropanol (10:1). The combined organic phases arewashed with brine and dried with magnesium sulfate. The solvent isevaporated and the residue is purified by column chromatography withether-pentane gradient or by preparative HPLC methods.

P: Reduction of Acids to Alcohols via Mixed Anhydride

According to Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15, p.4544, compound 94. A stirred solution of 11 mmol carboxylic acid(startmaterial) and triethylamine (1.9 mL, 14 mmol) in THF (300 mL) wasadded ethyl chloroformate (13 mL, 14 mmol) at −5° C. The mixture wasstirred for 20 min, and then sodium borohydride (1.72 g, 44 mmol) andmethanol (32 mL) were added consecutively. The mixture was stirred for30 min at −5° C., and then saturated NH₄Cl was added to quench thereaction. The mixture was extracted with Et2O (ca. 50 ml), and thecombined organic layers were washed with brine, dried over Na2SO4, andconcentrated. Flash chromatography (hexane/AcOEt 1/1) of the residuegave the desired product.

Q: Reduction of Oxazolidinones Towards N-Methyl Amino-alcohols

To a stirred solution of 5 mmol starting material (oxazolidinone) in 10ml THF were added 10 mmol lithium aluminium hydride at 0° C. Thereaction suspension was stirred for 4 h at room temperature. Thevigorously stirred reaction mixture was treated dropwisely with 10 ml ofa 1 m NaOH(aq) solution. The reaction mixture was stirred for 30 min andfiltered. The filtrate was concentrated and the residue was purified bysilica chromatography (ethyl acetate/hexane gradients).

S: Reduction of Esters Towards Alcohols

To a solution of 15 mmol (555 mg) NaBH4 in 15 ml water/THF (1:1) isadded 10 mmol ester (starting material), dissolved in 20 ml THF, drop bydrop. The reaction micture is stirred for 4 hours. The reaction mixtureis poured into stirred mixture of ice-cold water and diethyl ether (200ml, 1:1). The organic phase is separated. The aqueous phase is extractedthree times with 10 ml diethyl ether. The combined organic phases arewashed with brine and dried with magnesium sulfate. The solvent isevaporated and the residue is purified by column chromatography withethyl acetate-hexane gradient.

T: Conversion of Alcohol to Corresponding Triflate

According to Chem. Eur. J. (2007), 13, 115-134:

Pyridine (0.25 ml, 3.13 mmol) and Tf₂O (0.32 ml, 1.88 mmol) weresuccessively added to a solution of starting material (1.34 mmol) inCH₂Cl₂ (50 mL) at −20° C. and the resulting mixture was stirred for 1 hat that temperature. The pale pink solution was transferred into aseparation funnel containing aq. KHSO₄ (30 mL, 10%) and ice. The aqueouslayer was extracted with CH₂Cl₂, the combined organic phases were driedover Na₂SO₄, and the solvent was carefully evaporated while keeping thetemperature at 0° C. The desired product is filtered through a silicabed using ethyl acetate hexane solvent mixture.

U: Reduction of Mesylate Towards Alkane

Similar to Org. Lett.; 2004; 6(24) pp 4439-4442:

To a solution of starting material (0.5 mmol) in anhydrous ether (20 mL)was added lithium aluminium hydride (65 mg) at 0° C., stirred for 24 hat the same temperature. After addition of 0.263 ml 2M NaOH solution at−10° C. the reaction mixture was stirred for 30 min at room temperatureand filtered. The filtrate was concentrated and the residue was usedwithout further purification.

V: Fluorination of Secondary Alcohol (DBU/NfF):

According to Tetrahedron Letters, Vol. 36, No. 15, pp. 2611-2614, 1995:

To a cooled solution of secondary alcohol (2.5 mmol) and DBU (1.12 mL,7.5 mmol) in toluene (20 mmol), C₄F₉SO₂F(nona-fluoro-butyl-sulfonyl-fluorid) (1.13 g, 3.75 mmol) was added withstirring at 0° C. After 1 h at 0° C., the reaction mixture wasevaporated in vacuo and the residue chromatographed inhexane/ethylacetate gradient on a silica column.

For the following examples, NMR spectra were recorded on 400 MHz, 600MHz (¹H), 100 MHz and 151 MHz (¹³C) NMR instruments. ¹H NMR spectra werereferenced internally on CDCl₃ (δ¹H 7.26) and ¹³C NMR spectra werereferenced internally on CDCl₃ (δ¹³C 77.20). Liquid chromatographicanalysis (LC) was performed with a Merck-Hitachi gradient pump and aMerck-Hitachi, L-4000 variable wavelength UV-detector. A p-Bondapak C-18column (300×7.8 mm, 10 μm; waters instruments) was used with a flow of 2ml/min. LC-MS was performed using a Waters Quattra-Tof Premier micromass coupled with Waters Acquity HPLC instrument. The ionization modeused was electro spray positive ionization (ESI+). Analytical TLC wascarried out on 0.25 mm silica gel plates.

All solvents and chemicals were obtained from commercial sources andused without further purification.

Example 1 a) Synthesis of((S)-1-Hydroxymethyl-2-phenyl-ethyl)-methyl-carbamic Acid Tert-butylEster (1a)

(S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-phenyl-propionic acid (Fluka)is reduced according to general method P to obtain compound 1a in 80%yield (8.8 mmol, 2.34 g).

MS-ESI: 266 (M⁺+1, 100).

Elementary analysis:

Calculated: C 67.90% H 8.74% N 5.28% Determined: C 67.87% H 8.72% N5.27%

b) Synthesis of (S)-2-Methylamino-3-phenyl-propan-1-ol (1b)

Compound 1a is deproteted according to general procedure M to obtaincompound 1b in 77% yield (630 mg, 3.8 mmol).

MS-ESI: 166 (M⁺+1, 100).

Elementary analysis:

Calculated: C 72.69% H 9.15% N 8.48% Determined: C 72.66% H 9.13% N8.47%

c) Synthesis of (S)-2-(Methyl-prop-2-ynyl-amino)-3-phenyl-propan-1-ol(1c)

Compound 1c is synthesized according to general procedure H fromstarting material 1b using 2.5 mmol of propargyl bromide (298 mg). Thedesired compound is obtained in 60% yield (243 mg, 1.2 mmol).

MS-ESI: 204 (M⁺+1, 100).

Elementary analysis:

Calculated: C 76.81% H 8.43% N 6.89% Determined: C 76.77% H 8.42% N6.88%

d) Synthesis of Methanesulfonic Acid(S)-2-(methyl-prop-2-ynyl-amino)-3-phenyl-propyl Ester (1d)

Compound 1d is synthesized by general procedure I from starting material1c in 91% yield (126 mg, 0.45 mmol).

MS-ESI: 282 (M⁺+1, 100).

Elementary analysis:

Calculated: C 59.76% H 6.81% N 4.98% Determined: C 59.78% H 6.82% N4.99%

e) Synthesis of((S)-1-Fluoromethyl-2-phenyl-ethyl)-methyl-prop-2-ynyl-amine (1e)

Compound 1e is synthesized by general procedure A from starting material1d in 48% yield (24 mg, 0.12 mmol).

MS-ESI: 206 (M⁺+1, 100).

Elementary analysis:

Calculated: C 76.07% H 7.86% N 6.82% Determined: C 76.04% H 7.85% N6.83%

f) Synthesis of ((S)-[¹⁸F]1-Fluoromethyl-2-phenyl-ethyl)-methyl-prop-2-ynyl-amine (1e)

Compound 1f is prepared from compound 1e by general procedure B. Thedesired product 1e is obtained with 254 MBq starting from 1.12 GBq F-18fluoride (decay corrected).

g) Synthesis of (2S)-2-(methylamino)-3-phenylpropan-1-ol (1b)

To a solution of N-methyl-L-phenylalanine (Sigma, 10 g, 55.8 mmol) indry THF (600 mL) was added 3.18 g (83.7 mmol) lithium aluminium hydrideat −5° C. The reaction mixture was stirred over night and cooled to −5°C. Additional 2.12 g (55.8 mmol) lithium alanate were added. Thereaction mixture was refluxed overnight and cooled then to −5° C. Tothis mixture was added 21.5 ml NaOH solution (2N) drop by drop. andstirred at room temperature for additional 30 min. The mixture wasfiltered and the filtercake was washed with diethyl ether (50 mL). Thefiltrate was dried over MgSO₄ and solvent was removed under reducedpressure to obtain the product 1b as light yellow solid.

MS-ESI: 204 (M⁺+1, 100).

Elementary analysis:

Calculated: C 72.69% H 9.15% N 8.48% Determined: C 72.65% H 9.13% N8.45%

h) Synthesis of a Mixture ofN-[(2S)-1-chloro-3-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (1 h)and N-(2-chloro-3-phenylpropyl)-N-methylprop-2-yn-1-amine (1i)

To a stirred solution of 1c (100 mg, 0.49 mmol) and triethyl amine (1.0mmol), in THF (2 ml) was stirred at room temperature for 30 min. To thestirred mixture mesylchloride (0.60 mmol) was added drop wise at −7° C.and the reaction mixture was stirred at room temperature for additional30 min. Saturated Na₂CO₃ solution (1 mL) was added and stirred for 30more min. The organic layer was partitioned between CH2Cl2 (15 ml) andwater (10 ml). The organic phase was separated and washed with saturatedNaHCO₃ (10 ml) and brine (10 ml) and dried over MgSO₄ and filtered. Thesolvent was removed under reduced pressure to obtain the crude productas light yellow oil. The crude product was purified by silica-gel columnchromatography (hexane/ether 3:1) and analyzed by NMR, HPLC and LC-MS.The final product was obtained as mixture of 1h and 1i.

1h:

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.21 (t, J=2.38 Hz, 1 H) 2.38 (s, 3H) 2.73 (d, J=6.97 Hz, 2 H) 2.95 (dd, J=14.31, 8.07 Hz, 1 H) 3.23 (dd,J=14.31, 4.77 Hz, 1 H) 3.43 (dd, J=10.45, 2.38 Hz, 2 H) 4.10-4.18 (m, 1H) 7.28-7.35 (m, 5 H)

¹³C NMR (151 MHz, CHLOROFORM-d) δ ppm 34.77 (1 C) 38.29 (1 C) 43.58 (1C) 44.24 (s, 1C) 64.28 (1 C) 73.37 (1 C) 79.24 (1 C) 126.38 (1 C) 128.54(1 C) 129.24 (1 C) 138.86 (1 C)

1i

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.21 (t, J=2.38 Hz, 1H) 2.38 (s, 3H) 2.73 (d, J=6.97 Hz, 2 H) 2.95 (dd, J=14.31, 8.07 Hz, 1 H) 3.23 (dd,J=14.31, 4.77 Hz, 1 H) 3.43 (dd, J=10.45, 2.38 Hz, 2 H) 4.10-4.18 (m, 1H) 7.28-7.35 (m, 5 H)

¹³C NMR (151 MHz, CHLOROFORM-d) δ ppm 42.08 (1 C) 42.33 (1 C) 45.94 (1C) 60.43 (1 C) 61.52 (1 C) 73.49 (1 C) 77.98 (1 C) 126.76 (1 C) 128.33(1 C) 129.50 (1 C) 138.94 (1 C)

i) Synthesis ofN-[(2S)-1-fluoro-3-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (1e) andN-(2-fluoro-3-phenylpropyl)-N-methylprop-2-yn-1-amine (1k)

To the stirred solution of 1c (300 mg, 1.48 mmol) in dichloromethane (5mL) DAST (2.0 mmol) was added drop wise at −5° C. and the reactionmixture was stirred for additional 20 min at the same temperature.Saturated sodium carbonate (4.0 mL) was added to quench the untreatedDAST. The organic layer was partitioned between CH₂Cl₂ (25 ml) and water(15 ml). The organic phase was separated and washed with brine (10 ml)and dried over MgSO₄ and filtered. The solvent was removed under reducedpressure to obtain the crude product as light yellow oil. The crudeproduct was purified by silica-gel column chromatography (hexane/ether3:1) to obtain 1e and 1k as isolated products (compare TLC: FIG. 15).

1e:

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.27 (t, 1 H) 2.52 (s, 3H) 2.74(dd, J=13.39, 10.09 Hz, 1 H) 2.97-3.03 (m, 1 H) 3.03-3.14 (m, 1 H) 3.53(t, J=2.75 Hz, 2 H) 4.38 (ddd, J=47.32, 10.09, 4.95 Hz, 1 H) 4.51 (ddd,J=48.05, 10.27, 2.57 Hz, 1 H).

¹³C NMR (151 MHz, CHLOROFORM-d) δ ppm 32.91 (d, J=6.13 Hz, 1 C) 38.20(d, J=1.67 Hz, 1 C) 43.94 (d, J=2.23 Hz, 1 C) 63.83 (d, J=17.54 Hz, 1 C)72.83 (1 C) 80.15 (s, 1 C) 82.27 (d, J=172.08 Hz, 1 C) 126.31 (1 C)128.51 (1 C) 129.24 (1 C) 139.01 (1 C).

1k:

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.21 (t, J=2.38 Hz, 1 H) 2.37 (s, 3H) 2.59-2.72 (m, 2 H) 2.90-3.01 (m, 2 H) 3.41 (dd, J=4.95, 2.38 Hz, 2 H)4.75-4.89 (m, 1 H) 7.20-7.32 (m, 5H).

¹³C NMR (151 MHz, CHLOROFORM-d) δ ppm 39.66 (d, J=21.44 Hz, 1 C) 42.40(d, J=1.39 Hz, 1 C) 46.30 (d, J=1.67 Hz, 1 C) 58.53 (d, J=20.88 Hz, 1 C)73.37 (s, 1 C) 78.22 (s, 1 C) 92.84 (d, J=173.19 Hz, 1 C) 126.63 (1 C)128.45 (1 C) 129.37 (1 C) 136.85 (d, J=4.46 Hz, 1 C).

j) Synthesis ofN-[(2S)-1-(¹⁸F)fluoro-3-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine(1f) and N-[2-(¹⁸F)fluoro-3-phenylpropyl]-N-methylprop-2-yn-1-amine (1m)

The crude products 1f and 1m were obtained according to genaralprocedure C. The products 1f and 1m were separated according to generalprocedure C and investigated separately after HPLC separation (compareHPLC chromatograms FIG. 11 and FIG. 12).

Example 2 a) Synthesis of(4R,5S)-4-Methyl-5-phenyl-3-prop-2-ynyl-oxazolidin-2-one (2a)

Compound 2a is synthesized from(4R,5S)-(+)-4-Methyl-5-phenyl-2-oxazolidinone (Aldrich) according togeneral procedure F using 15 mmol (1.79 g) propargyl bromide (Aldrich).

Compound 2a is obtained in 76% yield (7.6 mmol, 1.61 g).

MS-ESI: 216 (M⁺+1, 100).

Elementary analysis:

Calculated: C 72.54% H 6.09% N 6.51% Determined: C 72.52% H 6.11% N6.52%

b) Synthesis of(1S,2R)-2-(Methyl-prop-2-ynyl-amino)-1-phenyl-propan-1-ol (2b)

Compound 2b is synthesized by general procedure Q from starting material2a in 89% yield (0.91 g, 4.5 mmol).

MS-ESI: 204 (M⁺+1, 100).

Elementary analysis:

Calculated: C 76.81% H 8.43% N 6.89% Determined: C 76.82% H 8.41% N6.88%

c) Synthesis of methanesulfonic acid(1S,2R)-2-(methyl-prop-2-ynyl-amino)-1-phenyl-propyl ester (2c)

Compound 2c is synthesized by general procedure T from starting material2b in 78% yield (352 mg, 1.05 mmol).

MS-ESI: 336 (M⁺+1, 100).

Elementary analysis:

Calculated: C 50.14% H 4.81% N 4.18% Determined: C 50.17% H 4.82% N4.16%

d) Synthesis of((1R,2R)-[¹⁸F]-2-Fluoro-1-methyl-2-phenyl-ethyl)-methyl-prop-2-ynyl-amine(2d)

Compound 2d is prepared from compound 2c by general procedure B. Thedesired product 2d is obtained with 198 MBq starting from 1.09 GBq F-18fluoride (decay corrected).

e) Synthesis of((1R,2R)-2-Fluoro-1-methyl-2-phenyl-ethyl)-methyl-prop-2-ynyl-amine (2e)

Compound 2e is synthesized by general procedure V from starting material2b in 58% yield (297 mg, 1.45 mmol).

MS-ESI: 206 (M⁺+1, 100).

Elementary analysis:

Calculated: C 76.07% H 7.86% N 6.82% Determined: C 76.04% H 7.84% N6.83%

f) Synthesis ofN-[(1R,2R)-1-chloro-1-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (2f)

To a stirred solution of 2b (120 mg, 0.54 mmol) and triethyl amine (1.0mmol), in THF (2 ml) was stirred at room temperature for 30 min. To thestirred mixture mesylchloride (0.60 mmol) was added drop wise at −7° C.and the reaction mixture was stirred at room temperature for additional30 min. Saturated Na₂CO₃ solution (1 mL) was added and stirred for 30more min. The organic layer was partitioned between CH₂Cl₂ (15 ml) andwater (10 ml). The organic phase was separated and washed with saturatedNaHCO₃ (10 ml) and brine (10 ml) and dried over MgSO₄ and filtered. Thesolvent was removed under reduced pressure to obtain the crude productas light yellow oil. The crude product was purified by silica-gel columnchromatography (hexane/ether 3:1).

MS-ESI: 221 (M+35Cl+1,82).

Elementary analysis:

Calculated: C 70.42% H 7.27% Cl 15.99% N 6.32% Determined: C 70.38% H7.25% Cl 15.97% N 6.30%

g) Synthesis ofN-[(1S,2R)-1-(¹⁸F)fluoro-1-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine(2 g)

The desired product (2g) was obtained from 2f according to the generalprocedure C.

Example 3 a) Synthesis of4-Furan-2-ylmethyl-3-prop-2-ynyl-oxazolidin-2-one (3a)

Compound 3a is synthesized according to general procedure F in 4 mmolscale from starting material 4-furan-2-ylmethyl-oxazolidin-2-one (J. Am.Chem. Soc.; 125; 42; 2003; 12694-12695). The desired compound 3a isobtained in 60% yield (2.4 mmol) using 6 mmol propagyl bromide asalkylating agent.

MS-ESI: 205 (M⁺+1, 100).

Elementary analysis:

Calculated: C 64.38% H 5.40% N 6.83% Determined: C 64.41% H 5.41% N6.82%

b) Synthesis of 3-Furan-2-yl-2-(methyl-prop-2-ynyl-amino)-propan-1-ol(3b)

Compound 3b is synthesized by general procedure Q (half scale) fromstarting material 3a in 70% yield (338 mg, 1.75 mmol).

MS-ESI: 194 (M⁺+1, 100).

Elementary analysis:

Calculated: C 68.37% H 7.82% N 7.25% Determined: C 68.37% H 7.81% N7.26%

c) Methanesulfonic acid 3-furan-2-yl-2-(methyl-prop-2-ynyl-amino)-propylester (3c)

Compound 3c is synthesized by general procedure I from starting material3b in 88% yield (120 mg, 0.44 mmol).

MS-ESI: 272 (M⁺+1, 100).

Elementary analysis:

Calculated: C 53.12% H 6.32% N 5.16% Determined: C 53.15% H 6.34% N5.18%

d) Synthesis of1-Fluoromethyl-2-furan-2-yl-ethyl)-methyl-prop-2-ynyl-amine (3d)

Compound 3d is synthesized by general procedure A from starting material3c in 61% yield (29.9 mg, 0.153 mmol).

MS-ESI: 196 (M⁺+1, 100).

Elementary analysis:

Calculated: C 67.67% H 7.23% N 7.17% Determined: C 67.67% H 7.23% N7.18%

e) Synthesis of(1-Fluoromethyl-2-furan-2-yl-ethyl)-methyl-prop-2-ynyl-amine (3e)

Compound 3e is synthesized by general procedure A from starting material3c with F-18 fluoride 0.96 GBq. The desired compound is obtained (124MBq).

Example 4 a) Synthesis of (S)-4-Benzyl-3-prop-2-ynyl-oxazolidin-2-one(4a)

Compound 4a is synthesized by general procedure F from starting material(S)-4-Benzyl-oxazolidin-2-one (Aldrich) in 72% yield (1.58 g, 7.2 mmol).

MS-ESI: 216 (M⁺+1, 100).

Elementary analysis:

Calculated: C 72.54% H 6.09% N 6.51% Determined: C 72.51% H 6.08% N6.53%

b) (S)-2-(Methyl-prop-2-ynyl-amino)-3-phenyl-propan-1-ol (4b)

Compound 4b is synthesized by general procedure Q from 4a in 68% yield(690 mg, 3.4 mmol).

MS-ESI: 204 (M⁺+1, 100).

Elementary analysis:

Calculated: C 76.81% H 8.43% N 6.89% Determined: C 76.78% H 8.41% N6.90%

c) 4-Bromo-benzenesulfonic acid(S)-2-(methyl-prop-2-ynyl-amino)-3-phenyl-propyl ester (4c)

Compound 4c is synthesized by general procedure K from 4bp-bromo-benzene sulfonyl chloride in 47% yield (1.58 g, 1.41 mmol).

MS-ESI: 424 (M^(+Br-isotope) 80+1, 76).

Elementary analysis: C 54.03% H 4.77% N 3.32% Determined: C 54.03% H4.77% N 3.32%

Example 5 a) Synthesis of(S)-4-[4-(2-Methoxymethoxy-ethoxy)-benzyl]-oxazolidin-2-one (5a)

Compound 5a is synthesized by general procedure H from(S)-(−)-4-(4-hydroxybenzyl)-2-oxazolidinone (Tetrahedron; EN; 57; 39;2001; 8313-8322) and 2-bromo-ethyl-methoxy-methyl-ether (Aldrich) at10-fold scale in 77% yield (15.4 mmol, 4.33 g).

MS-ESI: 282 (M⁺+1, 100).

Elementary analysis:

Calculated: C 59.78% H 6.81% N 4.98% Determined: C 59.81% H 6.83% N4.97%

b) Synthesis of(S)-4-[4-(2-Methoxymethoxy-ethoxy)-benzyl]-3-prop-2-ynyl-oxazolidin-2-one(5b)

Compound 5b is synthesized by general procedure F from compound 5a in65% yield (6.5 mmol, 2.07 g).

MS-ESI: 320 (M⁺+1, 100).

Elementary analysis:

Calculated: C 63.94% H 6.63% N 4.39% Determined: C 63.92% H 6.64% N4.40%

c) Synthesis of(S)-3-[4-(2-Methoxymethoxy-ethoxy)-phenyl]-2-(methyl-prop-2-ynyl-amino)-propan-1-ol(5c)

Compound 5c is synthesized by general procedure Q from compound 5b in74% yield (3.7 mmol, 1.14 g).

MS-ESI: 308 (M⁺+1, 100).

Elementary analysis:

Calculated: C 66.43% H 8.20% N 4.56% Determined: C 66.46% H 8.21% N4.55%

d) Synthesis of{(R)-2-[4-(2-Methoxymethoxy-ethoxy)-phenyl]-1-methyl-ethyl}-methyl-prop-2-ynyl-amine(5d)

Compound 5d is synthesized by general sequential procedure I (at 5-foldscale) and U from compound 5c in 81% yield over two steps (2.02 mmol,589 mg).

MS-ESI: 292 (M⁺+1, 100).

Elementary analysis:

Calculated: C 70.07% H 8.65% N 4.81% Determined: C 70.11% H 8.63% N4.82%

e) Synthesis of2-{4-[(R)-2-(Methyl-prop-2-ynyl-amino)-propyl]-phenoxy}-ethanol (5e)

Compound 5e is synthesized by general sequential procedure N (at 4-foldscale) from compound 5d in 88% yield (1.76 mmol, 436 mg).

MS-ESI: 248 (M⁺+1, 100).

Elementary analysis:

Calculated: C 72.84% H 8.56% N 5.66% Determined: C 72.81% H 8.55% N5.67%

f) Methanesulfonic acid2-{4-[(R)-2-(methyl-prop-2-ynyl-amino)-propyl]-phenoxy}-ethyl ester (5f)

Compound 5f is synthesized by general sequential procedure I fromcompound 5e in 93% yield (0.47 mmol, 153 mg).

MS-ESI: 326 (M⁺+1, 100).

Elementary analysis:

Calculated: C 59.05% H 7.12% N 4.30% Determined: C 59.07% H 7.11% N4.30%

g) Synthesis of{(R)-2-[4-(2-Fluoro-ethoxy)-phenyl]-1-methyl-ethyl}-methyl-prop-2-ynyl-amine(5g)

Compound 5g is synthesized by general procedure A from compound 5f in61% yield (0.153 mmol, 38 mg).

MS-ESI: 250 (M⁺+1, 100).

Elementary analysis:

Calculated: C 72.26% H 8.09% N 5.62% Determined: C 72.22% H 8.07% N5.60%

h) Synthesis of[F-18]{(R)-2-[4-(2-Fluoro-ethoxy)-phenyl]-1-methyl-ethyl}-methyl-prop-2-ynyl-amine(5h)

Compound 5h is synthesized by general procedure B from compound 5f(isolated 210 MBq from 1.41 GBq).

Example 6 a) Synthesis of((R)-1-methyl-2-phenyl-ethyl)-prop-2-ynyl-amine (6a)

840 mg (4 mmol) ((R)-1-methyl-2-phenyl-ethyl)-prop-2-ynyl-ammoniumhydrochloride (Sigma) is dissolved in 10 ml dichloromethane and 1Maqueous sodium carbonate. The organic phase is separated. The aqueousphase is extracted three times with 10 ml dichloromathane. The combinedorganic phases are washed with brine and dried with magnesium sulfate.The crude product 6a is used without further purification.

b) (2-Fluoro-ethyl)-((R)-1-methyl-2-phenyl-ethyl)-prop-2-ynyl-amine (6b)

Compound 6b is synthesized by general procedure H from compound 6a in60% yield (1.2 mmol, 262 mg).

MS-ESI: 220 (M⁺+1, 100).

Elementary analysis:

Calculated: C 76.68% H 8.27% N 6.39% Determined: C 76.66% H 8.26% N6.38%

c) [F-18](2-Fluoro-ethyl)-((R)-1-methyl-2-phenyl-ethyl)-prop-2-ynyl-amine (6c)

Compound 6c is synthesized by general procedure G from compound 6a and[F-18]-2-fluoro-ethyl-bromide (Bioorg. Med. Chem.; 13; 20; 2005;5779-5786). The desired product 6c is obtained with 178 MBq startingfrom 1.98 GBq F-18 fluoride (decay corrected).

d) Synthesis of2-{[(2R)-1-phenylpropan-2-yl](prop-2-yn-1-yl)amino}ethanol (6d)

A mixture of desmethyldeprenyl (Sigma, 150 mg, 0.72 mmol) and NaOH (60mg, 1.5 mmol), in MeCN (5 ml) was stirred at room temperature for 30min. To the stirred mixture 1-bromo ethanol (1.0 mmol) was added and thereaction mixture was refluxed for overnight. The reaction mixture wasallowed to cool to room temperature and solvent was evaporated underreduced pressure. The residue was partitioned between CH₂Cl₂ (20 ml) andwater (10 ml). The organic phase was separated and washed with saturatedNaHCO₃ (10 ml) and brine (10 ml). The organic layer was dried over MgSO₄and filtered. The solvent was removed under reduced pressure to obtainthe crude product as a light yellow liquid. The crude product waspurified by silica-gel column chromatography (hexane/ether 8:2).

MS-ESI: 218 (M⁺+1, 100).

Elementary analysis:

Calculated: C 77.38% H 8.81% N 6.45% O 7.36% Determined: C 77.35% H8.79% N 6.43% O 7.35%

e) Synthesis ofN-(2-chloroethyl)-N-[(2R)-1-phenylpropan-2-yl]prop-2-yn-1-amine (6e)

A mixture of 2 (150 mg, 0.69 mmol) and triethyl amine (1.5 mmol), in THF(3 ml) was stirred at room temperature for 30 min. To the stirredmixture mesylchloride (1.4 mmol) was added drop wise at −7° C. and thereaction mixture was stirred at room temperature for additional 30 min.Saturated Na₂CO₃ solution (2 mL) was added and stirred for 30 more min.The organic layer was partitioned between CH2Cl2 (20 ml) and water (10ml). The organic phase was separated and washed with saturated NaHCO₃(10 ml) and brine (10 ml) and dried over MgSO₄ and filtered. The solventwas removed under reduced pressure to obtain the crude product as lightyellow oil. The crude product was purified by silica-gel columnchromatography (hexane/et her 3:1).

MS-ESI: 235 (M^(+Cl35), 100).

Elementary analysis:

Calculated: C 71.33% H 7.70% N 5.94% Determined: C 71.30% H 7.68% N5.92%

f) Synthesis ofN-(2-fluoroethyl)-N-[(2R)-1-phenylpropan-2-yl]prop-2-yn-1-amine (6b)

To a solution of N-[(2R)-1-phenylpropan-2-yl]prop-2-yn-1-aminiumchloride (Sigma 100 mg, 0.578 mmol) in dry DMF (2 mL) was added sodiumhydride (48.0 mg, 2 mmol). The reaction mixture was stirred at roomtemperature for 30 min, after which 1-bromo-2-fluoro ethane (0.85 mg,0.603 mmol) was added. The reaction mixture was stirred over night,diluted with water (10 mL) and extracted with CH₂Cl₂ (3×15 mL). Theorganic phase was separated and washed with saturated NaHCO₃ (15 ml) andbrine (15 ml) and dried over MgSO₄ and filtered. The solvent was removedunder reduced pressure to obtain the crude product as light yellow oil.The crude product was purified by silica-gel column chromatography(hexane/ether 80:20) and analyzed by NMR, HPLC and LC-MS.

MS-ESI: 220 (M⁺+1, 100).

Elementary analysis:

Calculated: C 76.68% H 8.27% N 6.39% Determined: C 76.65% H 8.25% N6.36%

g) Synthesis ofN-[2-(¹⁸F)fluoroethyl]-N-[(2R)-1-phenylpropan-2-yl]prop-2-yn-1-amine(6c)

The desired product 6c was obtained from 6e according to the generalprocedure C.

Example 7 a) Synthesis of(1R,2R)-2-[methyl(prop-2-yn-1-yl)amino]-1-phenylpropan-1-ol (7a)

A mixture of (1R,2R)pseudoehedrine 150 mg, 0.72 mmol) and NaOH (60 mg,1.5 mmol), in MeCN (5 ml) was stirred at room temperature for 30 min. Tothe stirred mixture prpargyl bromide (1.0 mmol) was added and thereaction mixture was refluxed for overnight. The reaction mixture wasallowed to cool to room temperature and solvent was evaporated underreduced pressure. The residue was partitioned between CH₂Cl₂ (20 ml) andwater (10 ml). The organic phase was separated and washed with saturatedNaHCO₃ (10 ml) and brine (10 ml). The organic layer was dried over MgSO₄and filtered. The solvent was removed under reduced pressure to obtainthe crude product as a light yellow liquid. The crude product 7a waspurified by silica-gel column chromatography (hexane/ether 8:2).

MS-ESI: 204 (M⁺+1, 100).

Elementary analysis:

Calculated: C 76.81% H 8.43% N 6.89% Determined: C 76.78% H 8.42% N6.88%

b) Synthesis ofN-[(1S,2R)-1-fluoro-1-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (7b)

To the stirred solution of 7a (150 mg, 0.74 mmol) in dichloromethane (3mL) DAST (1.0 mmol) was added drop wise at −5° C. and the reactionmixture was stirred for additional 20 min at the same temperature.Saturated sodium carbonate (2.0 mL) was added to quench the untreatedDAST. The organic layer was partitioned between CH₂Cl₂ (15 ml) and water(10 ml). The organic phase was separated and washed with brine (10 ml)and dried over MgSO₄ and filtered. The solvent was removed under reducedpressure to obtain the crude product as light yellow oil. The crudeproduct was purified by silica-gel column chromatography (hexane/ether4:1)

MS-ESI: 206 (M⁺+1, 100).

Elementary analysis:

Calculated: C 76.07% H 7.86% N 6.82% Determined: C 76.02% H 7.85% N6.81%

c) Synthesis ofN-[(1S,2R)-1-chloro-1-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (7c)

To a stirred solution of 7a (120 mg, 0.54 mmol) in THF (2 ml) triethylamine (1.0 mmol) was added. The mixture was stirred at room temperaturefor 30 min. To the stirred mixture mesylchloride (0.60 mmol) was addeddrop wise at −7° C. and the reaction mixture was stirred at roomtemperature for additional 30 min. Saturated Na₂CO₃ solution (1 mL) wasadded and stirred for 30 more min. The organic layer was partitionedbetween CH₂Cl₂ (15 ml) and water (10 ml). The organic phase wasseparated and washed with saturated NaHCO₃ (10 ml) and brine (10 ml) anddried over MgSO₄ and filtered. The solvent was removed under reducedpressure to obtain the crude product as light yellow oil. The crudeproduct 7c was purified by silica-gel column chromatography(hexane/ether 3:1).

MS-ESI: 221 (M⁺35Cl+1, 70).

Elementary analysis:

Calculated: C 70.42% H 7.27% Cl 15.99% N 6.32% Determined: C 70.39% H7.25% Cl 15.97% N 6.30%

Example 8 a) Synthesis of(3aS,8aR)-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3]oxathiazole 2,2-dioxide (8a)

To a stirred solution of 5g (33 mmol) commercially available(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol in 200 ml dichloromethane and9.3 ml (67 mmol) triethyl amine was added 3.25 ml (40 mmol)sulforylchloride (SO₂Cl₂) in 80 ml dichloromethane at −65° C. Thereaction mixture was stirred for 3 h and warmed slowly to roomtemperature and stirred at this temperature for 18 hours. Theprecipitate was filtered and the filtrate was washed three times withwater and then with brine, dried over magnesium sulphate andconcentrated. The residue was diluted in little dichloromethane andrecrystallizes in hexane. The product was purified by columnschromatography (ethyl acetate hexane 0:100→100:0) to obtain 2.2 g of thedesired product 8a.

MS-ESI: 212 (M⁺+1)

Elementary analysis:

Calculated: C 51.17% H 4.29% N 6.63% Determined: C 57.20% H 4.30% N6.61%

b) Synthesis of(3aS,8aR)-3-(prop-2-yn-1-yl)-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3]oxathiazole2,2-dioxide (8b)

To a stirred solution of 2.2 g (10.4 mmol) 8a in 120 mldimethylformamide was added 1.35 ml (22.8 mmol) prop-2-yn-1-ol and 6 g(22.8 mmol) triphenylphosphin and 4.42 ml (22.8 mmol) dipropan-2-yl(E)-diazene-1,2-dicarboxylate. The reaction mixture was stirred for 2 hand concentrated. The residue was purified by two subsequent columnchromatographies (ethyl acetate hexane1:20→2:1) to obtain 970 mg (37%)of the desired product 8b.

MS-ESI: 250 (M⁺+1)

Elementary analysis:

Calculated: C 57.82% H 4.45% N 5.62% Determined: C 57.85% H 4.46% N5.61%

c) Synthesis of[(1S,2S)-2-fluoro-2,3-dihydro-1H-inden-1-yl]prop-2-yn-1-ylsulfamic acid(8c)

To a stirred solution of 100 mg (0.4 mmol) 8b in 2 ml dry THF was added139 mg (0.44 mmol) tetrabutylammonium fluoride. The reaction mixture wasstirred for 90 min and concentrated. The residue was purified bypreparative HPLC. The desired product 8c was obtained in 10% yieldcontaining minor amounts of TBAF.

d) Synthesis of(1S,2S)-2-fluoro-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine (8d)

To a stirred solution of 100 mg (0.4 mmol) 8b in 2 ml dry THF was added139 mg (0.44 mmol) tetrabutylammonium fluoride at 0° C. The reactionmixture was stirred for 90 min and concentrated. 2 ml 3N sulphuric acidwas added and the solution was heated in microwave oven for 10 min. Thesolution was poured into 20 ml ice-cold and vigorously stirred 0.35 Nsodium hydroxide solution. The aqueous phase was extracted withdichloromethane-isopropyl alcohol mixture (10:1) and the organic phasewas dried over magnesium sulphate and concentrated. The residue Theresidue was purified by preparative HPLC to obtain the compound 8d as 14mg amount batch

e) Synthesis of(1S,2S)-2-(¹⁸F)fluoro-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine(8e)

The desired product 8e was obtained according to the general procedure E

The features of the present invention disclosed in the specification,the claims and/or in the accompanying drawings, may, both separately,and in any combination thereof, be material for realizing the inventionin various forms thereof.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The preceding preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the examples, all temperatures are set forthuncorrected in degrees Celsius and, all parts and percentages are byweight, unless otherwise indicated.

The entire disclosures of all applications, patents and publications,cited herein and of corresponding European application No. 07021042.2,filed Oct. 26, 2007, are incorporated by reference herein.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

The invention claimed is:
 1. A compound of formula Ia

wherein W is —CH₂—C≡CH; A is substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, G⁴-(C₂-C₄)alkynyl-,G⁴-(C₁-C₄)alkoxy-, (G⁴-(C₁-C₄)alkyl)aryl-, or G⁴-(C₁-C₄)alkoxy)aryl-,G¹, G², G³ and G⁴ are, independently and individually, at eachoccurrence, hydrogen, (C₁-C₄)alkyl, L, or —(C₁-C₆)alkyl-L, with theproviso that exactly one of G¹-G⁴ is L or —(C₁-C₆)alkyl-L, L is aleaving group, or L is F, n is an integer from 0 to 6, and m is aninteger from 1 to 4, or a pharmaceutically acceptable salt, ester,amide, or complex thereof.
 2. The compound according to claim 1, whereinA is substituted or unsubstituted phenyl, substituted or unsubstitutedfuranyl, G⁴-(C₃-C₄)alkynyl-, G⁴-(C₁-C₃)alkoxy-,(G⁴-(C₁-C₃)alkyl)phenyl-, or (G⁴-(C₁-C₃)alkoxy)phenyl-.
 3. The compoundaccording to claim 2, wherein A is substituted or unsubstituted phenyl,substituted or unsubstituted furanyl, (G⁴-(C₁-C₃)alkyl)phenyl-,(G⁴-(C₁-C₃)alkoxy)phenyl-, hydroxy-phenyl, halo-phenyl, methoxy-phenyl,dimethoxy-phenyl, trifluormethyl-phenyl, or ((C₁-C₄)alkyl)-phenyl. 4.The compound according to claim 3, wherein A is substituted orunsubstituted phenyl, (G⁴-(C₁-C₃)alkoxy)phenyl-, hydroxyl-phenyl,fluorophenyl, methoxyphenyl, or methylphenyl.
 5. The compound accordingto claim 1, wherein G¹, G², G³ and G⁴ are independently andindividually, at each occurrence, hydrogen, (C₁-C₄)alkyl, L, or—(C₁-C₄)alkyl-L, with the proviso that exactly one of G¹-G⁴ is L or—(C₁-C₄)alkyl-L.
 6. The compound according to claim 5, wherein G¹, G²,G³ and G⁴ are independently and individually, at each occurrence,hydrogen, methyl, L, or —(C₁-C₂)alkyl-L, with the proviso that exactlyone of G¹-G⁴ is L or —(C₁-C₂)alkyl-L.
 7. The compound according to claim6, wherein G¹, G², G³ and G⁴ are independently and individually, at eachoccurrence, hydrogen, methyl, L, or -methyl-L, with the proviso thatexactly one of G¹-G⁴ is L or -methyl-L.
 8. The compound according toclaim 1, wherein L is halo, mesyloxy, tosyloxy,trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy,(4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy,(2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy,(2,4,6-tri-isopropyl-phenyl)sulfonyloxy,(2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, or(4-methoxy-phenyl)sulfonyloxy.
 9. The compound according to claim 8,wherein L is chloro, bromo, mesyloxy, tosyloxy,trifluormethylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy,(4-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, or(2,4,6-tri-isopropyl-phenyl) sulfonyloxy.
 10. The compound according toclaim 1 which is


11. The compound according to claim 1, wherein L is not F.
 12. Thecompound according to claim 1, wherein L is ¹⁸F.
 13. The compoundaccording to claim 1, wherein L is ¹⁹F.
 14. A composition comprising acompound according to claim 1 and a pharmaceutically acceptable carrieror diluent.
 15. A composition comprising a compound according to claim12 and a pharmaceutically acceptable carrier or diluent.
 16. Acomposition comprising a compound according to claim 13 and apharmaceutically acceptable carrier or diluent.
 17. A compositioncomprising a compound according to claim 11 and a pharmaceuticallyacceptable carrier or diluent.
 18. A kit comprising a sealed vialcontaining a predetermined quantity of a compound according to claim 11.19. A method for detecting the presence of monoamine oxidase in apatient's body, comprising: introducing into said patient's body adetectable amount of a compound according to claim 12 and detecting saidcompound by positron emission tomography (PET).
 20. A method oftreatment of a disease of the central nervous system comprising the stepof introducing into a patient a suitable quantity of a compoundaccording to claim
 1. 21. A method of treatment of a disease of thecentral nervous system comprising the step of introducing into a patienta suitable quantity of a compound according to claim
 12. 22. A method oftreatment of a disease of the central nervous system comprising the stepof introducing into a patient a suitable quantity of a compoundaccording to claim
 13. 23. The compound according to claim 13, whereinsaid compound contains exactly one ¹⁹F-atom and the ¹⁹F-atom is attachedto an sp³-hybridized carbon atom.
 24. The compound according to claim 1,wherein n is 1-3.
 25. The compound according to claim 1, wherein n is1-2.
 26. The compound according to claim 1, wherein m is 1 to
 2. 27. Themethod according to claim 19, wherein said method is for imaging adisease of the central nervous system in said patient.
 28. The compoundaccording to claim 12, wherein said compound is selected from thefollowing compounds:


29. The compound according to claim 13, wherein said compound isselected from the following compounds:


30. A method of synthesizing a compound according to claim 12,comprising reacting one or more compounds of formula Ia wherein L is aleaving group with an F-fluorinating agent in which F is ¹⁸F.
 31. Themethod according to claim 30, wherein L is halo, mesyloxy, tosyloxy,trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy,(4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl) sulfonyloxy,(2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy,(2,4,6-tri-isopropyl-phenyl)sulfonyloxy,(2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, or(4-methoxy-phenyl)sulfonyloxy.
 32. The method according to claim 30,wherein L is chloro, bromo, or iodo.
 33. The method according to claim30, wherein said one or more compounds of formula Ia is or includes acompound wherein G² is L, and L is chloro, bromo, or iodo.
 34. Themethod according to claim 33, wherein the compound synthesized is onewherein G¹ is —(C₁-C₆)alkyl-L.
 35. The method according to claim 33,wherein the compound synthesized is one wherein G¹ is -methyl-L.
 36. Themethod according to claim 30, wherein said F-fluorinating agent is 4, 7,13, 16, 21, 24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, KF, HF,KH F₂, CsF, NaF or a tetraalkylammonium salt, wherein F is ¹⁸F.
 37. Amethod of synthesizing a compound according to claim 13, comprisingreacting one or more compounds of formula Ia wherein L is a leavinggroup with an F-fluorinating agent in which F is ¹⁹F.
 38. The methodaccording to claim 37, wherein L is halo, mesyloxy, tosyloxy,trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy,(4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy,(2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy,(2,4,6-tri-isopropyl-phenyl)sulfonyloxy,(2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, or(4-methoxy-phenyl)sulfonyloxy.
 39. The method according to claim 37,wherein L is chloro, bromo, or iodo.
 40. The method according to claim37, wherein said one or more compounds of formula Ia is or includes acompound wherein G² is L, and L is chloro, bromo, or iodo.
 41. Themethod according to claim 40, wherein the compound synthesized is onewherein G¹ is —(C₁-C₆)alkyl-L.
 42. The method according to claim 40,wherein the compound synthesized is one wherein G¹ is -methyl-L.
 43. Themethod according to claim 37, wherein said F-fluorinating agent is 4, 7,13, 16, 21, 24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, KF, HF,KH F₂, CsF, NaF or a tetraalkylammonium salt, wherein F is ¹⁹F.
 44. Themethod according to claim 30, wherein a mixture of the followingcompounds 42 and 43

is reacted with a ¹⁸F-fluorinating agent to obtain a mixture of thefollowing compounds 13 and 39